Hippocampal CA3-CA1 synaptic rescue via DHHC2-mediated PSD95 palmitoylation sta…

Mechanistic description

graph TD
A["DHHC2<br/>Palmitoyltransferase"] --> B["PSD95<br/>Palmitoylation"]
B --> C["Synaptic Scaffold<br/>Stabilization"]
C --> D["AMPAR/NMDAR<br/>Surface Expression"]
D --> E["CA3-CA1 Synaptic<br/>Transmission"]
E --> F["LTP<br/>Induction"]
F --> G["Memory<br/>Consolidation"]
H["A-beta Oligomers"] --> I["DHHC2<br/>Disruption"]
I --> J["PSD95<br/>Depalmitoylation"]
J --> K["PSD95<br/>Degradation"]
K --> L["AMPAR/NMDAR<br/>Internalization"]
L --> M["Synaptic Scaffold<br/>Destabilization"]
M --> N["LTP<br/>Deficit"]
N --> O["Memory<br/>Impairment"]
P["DHHC2 Overexpression or<br/>Small Molecule Activator"] --> Q["Restored PSD95<br/>Palmitoylation"]
Q --> R["Synaptic Scaffold<br/>Re-stabilization"]
R --> S["Synaptic<br/>Function"]
S --> T["Cognitive<br/>Recovery"]
style A fill:#ce93d8,stroke:#9c27b0,color:#fff
style H fill:#ef5350,stroke:#c62828,color:#fff
style O fill:#ef5350,stroke:#c62828,color:#fff
style P fill:#81c784,stroke:#388e3c,color:#fff
style T fill:#ffd54f,stroke:#f57f17,color:#000

Mechanism / pathway

Evidence for (53)

• Adult hippocampal neurogenesis is impaired in AD

  PMID:35503338 2022 Zool Res

  Adult neurogenesis is the creation of new neurons which integrate into the existing neural circuit of the adult brain. Recent evidence suggests that adult hippocampal neurogenesis (AHN) persists throughout life in mammals, including humans. These newborn neurons have been implicated to have a crucial role in brain functions such as learning and memory. Importantly, studies have also found that hippocampal neurogenesis is impaired in neurodegenerative and neuropsychiatric diseases. Alzheimer's disease (AD) is one of the most common forms of dementia affecting millions of people. Cognitive dysfunction is a common symptom of AD patients and progressive memory loss has been attributed to the degeneration of the hippocampus. Therefore, there has been growing interest in identifying how hippocampal neurogenesis is affected in AD. However, the link between cognitive decline and changes in hippocampal neurogenesis in AD is poorly understood. In this review, we summarized the recent literature

• Hippocampal circuit mapping reveals CA3-CA1 dysfunction in AD models

  PMID:41082949 2025 Neurobiol Dis

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder with growing major health impacts in countries with aging populations. Existing therapeutic approaches that have been based on neurochemical and neuropathological findings are largely ineffective. This lack of progress suggests we require a new framework for future AD therapies. The examination of neural circuit mechanisms in AD mouse models is an emerging focus for identifying new AD treatment strategies. We now know there are neural circuit-level maladaptive alterations in AD brains, some of which appear very early in the disease process before neuropathological features are detectable. Recent advancements in viral-genetic technologies allow us to quantitatively map the cell-type-specific neural circuit connections in AD mouse models. Monosynaptic rabies virus mapping reveals age-progressive changes in both long-range and local hippocampal neural circuit connectivity in AD mouse models - and provides explanations fo

• Visual circuit activation via glymphatic modulation improves memory

  PMID:39747869 2025 Nat Commun

  Alzheimer's disease is characterized by progressive amyloid deposition and cognitive decline, yet the pathological mechanisms and treatments remain elusive. Here we report the therapeutic potential of low-intensity 40 hertz blue light exposure in a 5xFAD mouse model of Alzheimer's disease. Our findings reveal that light treatment prevents memory decline in 4-month-old 5xFAD mice and motivation loss in 14-month-old 5xFAD mice, accompanied by restoration of glial water channel aquaporin-4 polarity, improved brain drainage efficiency, and a reduction in hippocampal lipid accumulation. We further demonstrate the beneficial effects of 40 hertz blue light are mediated through the activation of the vLGN/IGL-Re visual circuit. Notably, concomitant use of anti-Aβ antibody with 40 hertz blue light demonstrates improved soluble Aβ clearance and cognitive performance in 5xFAD mice. These findings offer functional evidence on the therapeutic effects of 40 hertz blue light in Aβ-related pathologies

• Hyperactive neuronal autophagy depletes BDNF and impairs adult hippocampal neurogenesis in a corticosterone-induced mouse model of depression.

  PMID:36793868 2023 Theranostics

  Background: Depression is a mental disorder that poses a serious threat to human health. Adult hippocampal neurogenesis (AHN) is closely associated with the efficacy of antidepressants. Chronic treatment with corticosterone (CORT), a well-validated pharmacological stressor, induces depressive-like behaviors and suppresses AHN in experimental animals. However, the possible mechanisms of chronic CORT action remain elusive. Methods: A chronic CORT treatment (0.1 mg/mL, drinking water for 4 weeks) was applied to prepare a mouse model of depression. Immunofluorescence was performed to analyze the hippocampal neurogenesis lineage, and immunoblotting, immunofluorescence, electron microscopy, and adeno-associated virus (AAV) expressing a pH-sensitive tandemly tagged light chain 3 (LC3) protein were used to analyze neuronal autophagy. AAV-hSyn-miR30-shRNA was used to knock down autophagy-related gene 5 (Atg5) expression in the neurons. Results: Chronic CORT induces depressive-like behaviors and

• Astrocytes and brain-derived neurotrophic factor (BDNF).

  PMID:36780947 2023 Neurosci Res

  Astrocytes are emerging in the neuroscience field as crucial modulators of brain functions, from the molecular control of synaptic plasticity to orchestrating brain-wide circuit activity for cognitive processes. The cellular pathways through which astrocytes modulate neuronal activity and plasticity are quite diverse. In this review, we focus on neurotrophic pathways, mostly those mediated by brain-derived neurotrophic factor (BDNF). Neurotrophins are a well-known family of trophic factors with pleiotropic functions in neuronal survival, maturation and activity. Within the brain, BDNF is the most abundantly expressed and most studied of all neurotrophins. While we have detailed knowledge of the effect of BDNF on neurons, much less is known about its physiology on astroglia. However, over the last years new findings emerged demonstrating that astrocytes take an active part into BDNF physiology. In this work, we discuss the state-of-the-art knowledge about astrocytes and BDNF. Indeed, as

• Metrnl regulates cognitive dysfunction and hippocampal BDNF levels in D-galactose-induced aging mice.

  PMID:36229598 2023 Acta Pharmacol Sin

  Aging is one of the main risk factors for cognitive dysfunction. During aging process, the decrease of brain-derived neurotrophic factor (BDNF) and the impairment of astrocyte function contribute to the cognitive impairment. Metrnl, a neurotrophic factor, promotes neural growth, migration and survival, and supports neural function. In this study, we investigated the role of Metrnl in cognitive functions. D-galactose (D-gal)-induced aging model was used to simulate the process of aging. Cognitive impairment was assessed by the Morris water maze test. We showed that Metrnl expression levels were significantly increased in the hippocampus of D-gal-induced aging mice. Metrnl knockout did not affect the cognitive functions in the baseline state, but aggravated the cognitive impairment in the D-gal-induced aging mice. Furthermore, Metrnl knockout significantly reduced hippocampal BDNF, TrkB, and glial fibrillary acidic protein (GFAP) levels in the D-gal-induced aging mice. In the D-gal-induc

• IL4-driven microglia modulate stress resilience through BDNF-dependent neurogenesis.

  PMID:33731342 2021 Sci Adv

  Adult neurogenesis in the dentate gyrus of the hippocampus is regulated by specific microglia groups and functionally implicated in behavioral responses to stress. However, the role of microglia in hippocampal neurogenesis and stress resilience remains unclear. We identified interleukin 4 (IL4)-driven microglia characterized by high expression of Arg1, which is critical in maintaining hippocampal neurogenesis and stress resistance. Decreasing Arg1+ microglia in the hippocampus by knocking down the microglial IL4R suppressed hippocampal neurogenesis and enhanced stress vulnerability. Increasing Arg1+ microglia in the hippocampus by enhancing IL4 signaling restored hippocampal neurogenesis and the resilience to stress-induced depression. Brain-derived neurotrophic factor (BDNF) was found necessary for the proneurogenesis effects of IL4-driven microglia. Together, our findings suggest that IL4-driven microglia in the hippocampus trigger BDNF-dependent neurogenesis responding to chronic st

• Neuronal extracellular vesicles and associated microRNAs induce circuit connectivity downstream BDNF.

  PMID:36753414 2023 Cell Rep

  Extracellular vesicles (EVs) have emerged as mediators of cellular communication, in part via the delivery of associated microRNAs (miRNAs), small non-coding RNAs that regulate gene expression. We show that brain-derived neurotrophic factor (BDNF) mediates the sorting of miR-132-5p, miR-218-5p, and miR-690 in neuron-derived EVs. BDNF-induced EVs in turn increase excitatory synapse formation in recipient hippocampal neurons, which is dependent on the inter-neuronal delivery of these miRNAs. Transcriptomic analysis further indicates the differential expression of developmental and synaptogenesis-related genes by BDNF-induced EVs, many of which are predicted targets of miR-132-5p, miR-218-5p, and miR-690. Furthermore, BDNF-induced EVs up-regulate synaptic vesicle (SV) clustering in a transmissible manner, thereby increasing synaptic transmission and synchronous neuronal activity. As BDNF and EV-miRNAs miR-218 and miR-132 were previously implicated in neuropsychiatric disorders such as anx

• Pharmacotherapy with fluoxetine restores functional connectivity from the dentate gyrus to field CA3 in the Ts65Dn mouse model of down syndrome.

  PMID:23620781 2013 PLoS One

  Down syndrome (DS) is a high-incidence genetic pathology characterized by severe impairment of cognitive functions, including declarative memory. Impairment of hippocampus-dependent long-term memory in DS appears to be related to anatomo-functional alterations of the hippocampal trisynaptic circuit formed by the dentate gyrus (DG) granule cells - CA3 pyramidal neurons - CA1 pyramidal neurons. No therapies exist to improve cognitive disability in individuals with DS. In previous studies we demonstrated that pharmacotherapy with fluoxetine restores neurogenesis, granule cell number and dendritic morphology in the DG of the Ts65Dn mouse model of DS. The goal of the current study was to establish whether treatment rescues the impairment of synaptic connectivity between the DG and CA3 that characterizes the trisomic condition. Euploid and Ts65Dn mice were treated with fluoxetine during the first two postnatal weeks and examined 45-60 days after treatment cessation. Untreated Ts65Dn mice had

• Functional Connectivity of Hippocampal CA3 Predicts Neurocognitive Aging via CA1-Frontal Circuit.

  PMID:32239141 2020 Cereb Cortex

  The CA3 and CA1 principal cell fields of the hippocampus are vulnerable to aging, and age-related dysfunction in CA3 may be an early seed event closely linked to individual differences in memory decline. However, whether the differential vulnerability of CA3 and CA1 is associated with broader disruption in network-level functional interactions in relation to age-related memory impairment, and more specifically, whether CA3 dysconnectivity contributes to the effects of aging via CA1 network connectivity, has been difficult to test. Here, using resting-state fMRI in a group of aged rats uncontaminated by neurodegenerative disease, aged rats displayed widespread reductions in functional connectivity of CA3 and CA1 fields. Age-related memory deficits were predicted by connectivity between left CA3 and hippocampal circuitry along with connectivity between left CA1 and infralimbic prefrontal cortex. Notably, the effects of CA3 connectivity on memory performance were mediated by CA1 connectiv

• Hippocampal neural circuit connectivity alterations in an Alzheimer's disease mouse model revealed by monosynaptic rabies virus tracing.

  PMID:35843448 2022 Neurobiol Dis

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder with growing major health impacts, particularly in countries with aging populations. The examination of neural circuit mechanisms in AD mouse models is a recent focus for identifying new AD treatment strategies. We hypothesize that age-progressive changes of both long-range and local hippocampal neural circuit connectivity occur in AD. Recent advancements in viral-genetic technologies provide new opportunities for semi-quantitative mapping of cell-type-specific neural circuit connections in AD mouse models. We applied a recently developed monosynaptic rabies tracing method to hippocampal neural circuit mapping studies in AD model mice to determine how local and global circuit connectivity to hippocampal CA1 excitatory neurons may be altered in the single APP knock-in (APP-KI) AD mouse model. To determine age-related AD progression, we measured circuit connectivity in age-matched littermate control and AD model mice at

• Profiling hippocampal neuronal populations reveals unique gene expression mosaics reflective of connectivity-based degeneration in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease.

  PMID:40078964 2025 Front Mol Neurosci

  INTRODUCTION: Individuals with Down syndrome (DS) exhibit neurological deficits throughout life including the development of in Alzheimer's disease (AD) pathology and cognitive impairment. At the cellular level, dysregulation in neuronal gene expression is observed in postmortem human brain and mouse models of DS/AD. To date, RNA-sequencing (RNA-seq) analysis of hippocampal neuronal gene expression including the characterization of discrete circuit-based connectivity in DS remains a major knowledge gap. We postulate that spatially characterized hippocampal neurons display unique gene expression patterns due, in part, to dysfunction of the integrity of intrinsic circuitry. METHODS: We combined laser capture microdissection to microisolate individual neuron populations with single population RNA-seq analysis to determine gene expression analysis of CA1 and CA3 pyramidal neurons and dentate gyrus granule cells located in the hippocampus, a region critical for learning, memory, and synapti

• Entorhinal-Hippocampal Circuit Integrity Is Related to Mnemonic Discrimination and Amyloid-β Pathology in Older Adults.

  PMID:36302636 2022 J Neurosci

  Mnemonic discrimination, a cognitive process that relies on hippocampal pattern separation, is one of the first memory domains to decline in aging and preclinical Alzheimer's disease. We tested whether functional connectivity (FC) within the entorhinal-hippocampal circuit, measured with high-resolution resting state fMRI, is associated with mnemonic discrimination and amyloid-β (Aβ) pathology in a sample of 64 cognitively normal human older adults (mean age, 71.3 ± 6.4 years; 67% female). FC was measured between entorhinal-hippocampal circuit nodes with known anatomical connectivity, as well as within cortical memory networks. Aβ pathology was measured with 18F-florbetapir-PET, and neurodegeneration was assessed with subregional volume from structural MRI. Participants performed both object and spatial versions of a mnemonic discrimination task outside of the scanner and were classified into low-performing and high-performing groups on each task using a median split. Low object mnemoni

• Monosynaptic Rabies Tracing Reveals Sex- and Age-Dependent Dorsal Subiculum Connectivity Alterations in an Alzheimer's Disease Mouse Model.

  PMID:38503494 2024 J Neurosci

  The subiculum (SUB), a hippocampal formation structure, is among the earliest brain regions impacted in Alzheimer's disease (AD). Toward a better understanding of AD circuit-based mechanisms, we mapped synaptic circuit inputs to dorsal SUB using monosynaptic rabies tracing in the 5xFAD mouse model by quantitatively comparing the circuit connectivity of SUB excitatory neurons in age-matched controls and 5xFAD mice at different ages for both sexes. Input-mapped brain regions include the hippocampal subregions (CA1, CA2, CA3), medial septum and diagonal band, retrosplenial cortex, SUB, postsubiculum (postSUB), visual cortex, auditory cortex, somatosensory cortex, entorhinal cortex, thalamus, perirhinal cortex (Prh), ectorhinal cortex, and temporal association cortex. We find sex- and age-dependent changes in connectivity strengths and patterns of SUB presynaptic inputs from hippocampal subregions and other brain regions in 5xFAD mice compared with control mice. Significant sex differences

• Synaptic plasticity and functional stabilization in the hippocampal formation: possible role in Alzheimer's disease.

  PMID:3278521 1988 Adv Neurol

  In this chapter we have explored the hypothesis that reactive synaptogenesis is an adaptive mechanism that can compensate for loss of a fraction of a defined neuronal population. Partial cell loss occurs during the course of aging, neurodegenerative diseases, and minor traumatic brain injuries. As cells are lost or as their function severely declines, new connections made by healthy neurons from within the population can assume parallel functions (homotypic sprouting), or fibers from converging pathways (heterotypic sprouting) can act to boost weakened signals and maintain functional stability. When cell death (or disease) progresses to the point where the pathway is broken, sprouting can no longer maintain information flow along the circuit and thus is unable to preserve function, unless new circuits can also be compensatory as, for example, after unilateral injury. We have analyzed the consequences of cell loss on the nature of circuit regrowth within the primary hippocampal circuits

• Selenium and brain aging: A comprehensive review with a focus on hippocampal neurogenesis.

  PMID:40946974 2025 Ageing Res Rev

  Brain aging is accompanied by progressive cognitive decline and increased risk of neurodegenerative diseases, with adult hippocampal neurogenesis (AHN) playing a pivotal role in maintaining cognitive resilience. Selenium, an essential trace element, exerts significant neuroprotective and neurogenic effects predominantly through its incorporation into selenoproteins, which regulate oxidative stress, neuroinflammation, and synaptic plasticity. This review synthesizes recent advances delineating selenium's metabolism, bioavailability, and its multifaceted roles in brain development, function, and aging, emphasizing mechanisms underpinning hippocampal neurogenesis. Key molecular pathways influenced by selenium include phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/Wingless/Integrated (Wnt) and brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling pathways that promote neural progenitor cell proliferation and differentiation. Selenium transport via

• Genetic removal of synaptic Zn(2+) impairs cognition, alters neurotrophic signaling and induces neuronal hyperactivity.

  PMID:36742045 2022 Front Neurol

  Vesicular Zn2+ (zinc) is released at synapses and has been demonstrated to modulate neuronal responses. However, mechanisms through which dysregulation of zinc homeostasis may potentiate neuronal dysfunction and neurodegeneration are not well-understood. We previously reported that accumulation of soluble amyloid beta oligomers (AβO) at synapses correlates with synaptic loss and that AβO localization at synapses is regulated by synaptic activity and enhanced by the release of vesicular Zn2+ in the hippocampus, a brain region that deteriorates early in Alzheimer's disease (AD). Significantly, drugs regulating zinc homeostasis inhibit AβO accumulation and improve cognition in mouse models of AD. We used both sexes of a transgenic mouse model lacking synaptic Zn2+ (ZnT3KO) that develops AD-like cognitive impairment and neurodegeneration to study the effects of disruption of Zn2+ modulation of neurotransmission in cognition, protein expression and activation, and neuronal excitability. Her

• Spatiotemporal resolution of BDNF neuroprotection against glutamate excitotoxicity in cultured hippocampal neurons.

  PMID:23384605 2013 Neuroscience

  Brain-derived neurotrophic factor (BDNF) protects hippocampal neurons from glutamate excitotoxicity as determined by analysis of chromatin condensation, through activation of extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3-K) signaling pathways. However, it is still unknown whether BDNF also prevents the degeneration of axons and dendrites, and the functional demise of synapses, which would be required to preserve neuronal activity. Herein, we have studied the time-dependent changes in several neurobiological markers, and the regulation of proteolytic mechanisms in cultured rat hippocampal neurons, through quantitative western blot and immunocytochemistry. Calpain activation peaked immediately after the neurodegenerative input, followed by a transient increase in ubiquitin-conjugated proteins and increased abundance of cleaved-caspase-3. Proteasome and calpain inhibition did not reproduce the protective effect of BDNF and caspase inhibition in prevent

• The intra-arterial injection of microglia protects hippocampal CA1 neurons against global ischemia-induced functional deficits in rats.

  PMID:16844302 2006 Neuroscience

  In the present study, we have attempted to elucidate the effects of the intra-arterial injection of microglia on the global ischemia-induced functional and morphological deficits of hippocampal CA1 neurons. When PKH26-labeled immortalized microglial cells, GMIR1, were injected into the subclavian artery, these exogenous microglia were found to accumulate in the hippocampus at 24 h after ischemia. In hippocampal slices prepared from medium-injected rats subjected to ischemia 48 h earlier, synaptic dysfunctions including a significant reduction of synaptic responses and a marked reduction of long-term potentiation (LTP) of the CA3-CA1 Schaffer collateral synapses were observed. At this stage, however, neither significant neuronal degeneration nor gliosis was observed in the hippocampus. At 96 h after ischemia, there was a total loss of the synaptic activity and a marked neuronal death in the CA1 subfield. In contrast, the basal synaptic transmission and LTP of the CA3-CA1 synapses were w

• Human Hippocampal Neurogenesis Persists throughout Aging.

  PMID:29625071 2018 Cell Stem Cell

  Adult hippocampal neurogenesis declines in aging rodents and primates. Aging humans are thought to exhibit waning neurogenesis and exercise-induced angiogenesis, with a resulting volumetric decrease in the neurogenic hippocampal dentate gyrus (DG) region, although concurrent changes in these parameters are not well studied. Here we assessed whole autopsy hippocampi from healthy human individuals ranging from 14 to 79 years of age. We found similar numbers of intermediate neural progenitors and thousands of immature neurons in the DG, comparable numbers of glia and mature granule neurons, and equivalent DG volume across ages. Nevertheless, older individuals have less angiogenesis and neuroplasticity and a smaller quiescent progenitor pool in anterior-mid DG, with no changes in posterior DG. Thus, healthy older subjects without cognitive impairment, neuropsychiatric disease, or treatment display preserved neurogenesis. It is possible that ongoing hippocampal neurogenesis sustains human-s

• Dynamics of hippocampal neurogenesis in adult humans.

  PMID:23746839 2013 Cell

  Adult-born hippocampal neurons are important for cognitive plasticity in rodents. There is evidence for hippocampal neurogenesis in adult humans, although whether its extent is sufficient to have functional significance has been questioned. We have assessed the generation of hippocampal cells in humans by measuring the concentration of nuclear-bomb-test-derived ¹⁴C in genomic DNA, and we present an integrated model of the cell turnover dynamics. We found that a large subpopulation of hippocampal neurons constituting one-third of the neurons is subject to exchange. In adult humans, 700 new neurons are added in each hippocampus per day, corresponding to an annual turnover of 1.75% of the neurons within the renewing fraction, with a modest decline during aging. We conclude that neurons are generated throughout adulthood and that the rates are comparable in middle-aged humans and mice, suggesting that adult hippocampal neurogenesis may contribute to human brain function.

• The relationship between adult hippocampal neurogenesis and cognitive impairment in Alzheimer's disease.

  PMID:39166771 2024 Alzheimers Dement

  Neurogenesis persists throughout adulthood in the hippocampus and contributes to specific cognitive functions. In Alzheimer's disease (AD), the hippocampus is affected by pathology and functional impairment early in the disease. Human AD patients have reduced adult hippocampal neurogenesis (AHN) levels compared to age-matched healthy controls. Similarly, rodent AD models show a decrease in AHN before the onset of the classical hallmarks of AD pathology. Conversely, enhancement of AHN can protect against AD pathology and ameliorate memory deficits in both rodents and humans. Therefore, impaired AHN may be a contributing factor of AD-associated cognitive decline, rather than an effect of it. In this review we outline the regulation and function of AHN in healthy individuals, and highlight the relationship between AHN dysfunction and cognitive impairments in AD. The existence of AHN in humans and its relevance in AD patients will also be discussed, with an outlook toward future research d

• Adult hippocampal neurogenesis in Alzheimer's disease: A roadmap to clinical relevance.

  PMID:36736288 2023 Cell Stem Cell

  Adult hippocampal neurogenesis (AHN) drops sharply during early stages of Alzheimer's disease (AD), via unknown mechanisms, and correlates with cognitive status in AD patients. Understanding AHN regulation in AD could provide a framework for innovative pharmacological interventions. We here combine molecular, behavioral, and clinical data and critically discuss the multicellular complexity of the AHN niche in relation to AD pathophysiology. We further present a roadmap toward a better understanding of the role of AHN in AD by probing the promises and caveats of the latest technological advancements in the field and addressing the conceptual and methodological challenges ahead.

• Aerobic Exercise Restores Hippocampal Neurogenesis and Cognitive Function by Decreasing Microglia Inflammasome Formation Through Irisin/NLRP3 Pathway.

  PMID:40192010 2025 Aging Cell

  Persistent microglial inflammation is a detrimental contributor to the progression of Parkinson disease (PD) pathology and related issues such as impaired adult hippocampal neurogenesis (AHN) and cognition. We conducted a 10-week exercise program with MPTP-treated mice to determine whether neuroinflammation can be addressed by aerobic exercise and elucidate its underlying regulatory mechanisms. Ten weeks of exercise significantly reduced PD-related pathology and enhanced AHN and memory. These changes were linked to a reduction in neuronal apoptosis, microglial inflammation, and NLRP3 inflammasome activation. In cultured microglia, fibril α-synuclein reduced FNDC5/irisin protein levels and induced NLRP3 inflammasome formation and IL-1β production, which could be diminished by recombinant irisin treatment. Interestingly, "runner serum" isolated from exercising rodents enhanced FNDC5/irisin expression and reduced NLRP3 inflammasome components and IL-1β secretion in α-synuclein-treated mic

• Latent toxoplasmosis impairs learning and memory yet strengthens short-term and long-term hippocampal synaptic plasticity at perforant pathway-dentate gyrus, and Schaffer collatterals-CA1 synapses.

  PMID:37268701 2023 Sci Rep

  Investigating long-term potentiation (LTP) in disease models provides essential mechanistic insight into synaptic dysfunction and relevant behavioral changes in many neuropsychiatric and neurological diseases. Toxoplasma (T) gondii is an intracellular parasite causing bizarre changes in host's mind including losing inherent fear of life-threatening situations. We examined hippocampal-dependent behavior as well as in vivo short- and long-term synaptic plasticity (STP and LTP) in rats with latent toxoplasmosis. Rats were infected by T. gondii cysts. Existence of REP-529 genomic sequence of the parasite in the brain was detected by RT-qPCR. Four and eight weeks after infection, spatial, and inhibitory memories of rats were assessed by Morris water maze and shuttle box tests, respectively. Eight weeks after infection, STP was assessed in dentate gyrus (DG) and CA1 by double pulse stimulation of perforant pathway and Shaffer collaterals, respectively. High frequency stimulation (HFS) was ap

• Deficits in synaptic function occur at medial perforant path-dentate granule cell synapses prior to Schaffer collateral-CA1 pyramidal cell synapses in the novel TgF344-Alzheimer's Disease Rat Model.

  PMID:29199135 2018 Neurobiol Dis

  Alzheimer's disease (AD) pathology begins decades prior to onset of clinical symptoms, and the entorhinal cortex and hippocampus are among the first and most extensively impacted brain regions. The TgF344-AD rat model, which more fully recapitulates human AD pathology in an age-dependent manner, is a next generation preclinical rodent model for understanding pathophysiological processes underlying the earliest stages of AD (Cohen et al., 2013). Whether synaptic alterations occur in hippocampus prior to reported learning and memory deficit is not known. Furthermore, it is not known if specific hippocampal synapses are differentially affected by progressing AD pathology, or if synaptic deficits begin to appear at the same age in males and females in this preclinical model. Here, we investigated the time-course of synaptic changes in basal transmission, paired-pulse ratio, as an indirect measure of presynaptic release probability, long-term potentiation (LTP), and dendritic spine density

• A computational study on plasticity during theta cycles at Schaffer collateral synapses on CA1 pyramidal cells in the hippocampus.

  PMID:25220633 2015 Hippocampus

  Cellular activity in the CA1 area of the hippocampus waxes and wanes at theta frequency (4-8 Hz) during exploratory behavior of rats. Perisomatic inhibition onto pyramidal cells tends to be strongest out of phase with pyramidal cell activity, whereas dendritic inhibition is strongest in phase with pyramidal cell activity. Synaptic plasticity also varies across the theta cycle, from strong long-term potentiation (LTP) to long-term depression (LTD), putatively corresponding to encoding and retrieval phases for information patterns encoded by pyramidal cell activity (Hasselmo et al. (2002a) Neural Comput 14:793-817). The mechanisms underpinning the phasic changes in plasticity are not clear, but it is likely that inhibition plays a role by affecting levels of electrical activity and calcium concentration at synapses. We explore the properties of synaptic plasticity during theta at Schaffer collateral synapses on CA1 pyramidal neurons and the influence of spatially and temporally targeted

• Recognition Memory Induces Natural LTP-like Hippocampal Synaptic Excitation and Inhibition.

  PMID:36142727 2022 Int J Mol Sci

  Synaptic plasticity is a cellular process involved in learning and memory by which specific patterns of neural activity adapt the synaptic strength and efficacy of the synaptic transmission. Its induction is governed by fine tuning between excitatory/inhibitory synaptic transmission. In experimental conditions, synaptic plasticity can be artificially evoked at hippocampal CA1 pyramidal neurons by repeated stimulation of Schaffer collaterals. However, long-lasting synaptic modifications studies during memory formation in physiological conditions in freely moving animals are very scarce. Here, to study synaptic plasticity phenomena during recognition memory in the dorsal hippocampus, field postsynaptic potentials (fPSPs) evoked at the CA3-CA1 synapse were recorded in freely moving mice during object-recognition task performance. Paired pulse stimuli were applied to Schaffer collaterals at the moment that the animal explored a new or a familiar object along different phases of the test. S

• Learning as a Functional State of the Brain: Studies in Wild-Type and Transgenic Animals.

  PMID:29080022 2017 Adv Exp Med Biol

  Contemporary neuroscientists are paying increasing attention to subcellular, molecular, and electrophysiological mechanisms underlying learning and memory processes. Recent studies have examined the development of transgenic mice affected at different stages of the learning process, or have emulated in animals various human pathological conditions involving cognition and motor learning. However, a parallel effort is needed to develop stimulating and recording techniques suitable for use in behaving mice in order to understand activity-dependent synaptic changes taking place during the very moment of the learning process. The in vivo models should incorporate information collected from different molecular and in vitro approaches. Long-term potentiation (LTP) has been proposed as the neural mechanism underlying synaptic plasticity, and NMDA receptors have been proposed as the molecular substrate of LTP. It now seems necessary to study the relationship of both LTP and NMDA receptors to fu

• Cannabidiol and pBDNF Cotreatment Attenuates Pathological Symptoms and Improves Cognition in 3 month-Old 5XFAD Mice.

  PMID:41924980 2026 ACS Chem Neurosci

  The marginal efficiency observed with the existing therapies in Alzheimer's Disease (AD) can be attributed to the timing of the treatment. The beneficiaries of symptomatic or disease-modifying therapy for AD are mild-cognitive-impairment (MCI) or late-stage dementia patients. At this stage, the pathological features are already advanced and irreversible, as the shift in biomarker levels starts in a continuum 15-20 years prior. Early intervention, therefore, is a plausible solution to this issue. Consequently, we selected 3 month-old 5XFAD AD mice as an early intervention model. We administered cannabidiol (CBD) and plasmid brain-derived neurotrophic factor (BDNF) encapsulated in liposome nanoparticles, functionalized with penetratin and mannose for brain-targeting, as a therapy. Neuroinflammation is emerging as a key driver of AD progression by its interaction with amyloid plaques and phosphorylated tau. Therefore, CBD, which is anti-inflammatory and neuroprotective, was used. BDNF, a

• Neurotransmitter dysregulation in depression, anxiety, and suicidality: From synaptic dysfunction to cellular pathogenesis.

  PMID:41924767 2026 Psychiatry Res

  Affective disorders such as depression, anxiety disorders and suicidality are major contributors to global psychiatry. The "chemical imbalance" theory has been traditionally used; however recent research suggests that neurotransmitter dysfunction may represent an important early contributor within a broader, bidirectional cascade of cellular changes. Stress responses and neural circuits are disrupted by dysregulation of the serotonergic, noradrenergic, dopaminergic, GABAergic, and glutamatergic systems, which leads to oxidative stress, excitotoxicity, neuroinflammation, and decreased trophic support. Reduced brain-derived neurotrophic factor (BDNF) signaling, dendritic retraction, synapse loss, and apoptotic susceptibility are the common pathways that result in both amygdala hyperactivity and structural atrophy in the hippocampus and prefrontal cortex. Rumination, fear, anhedonia, cognitive impairment, and suicidal ideation are clinical manifestations of the ensuing circuit failure. Th

• TrkB promotes the neuronal secretion of soluble Siglec-2 (CD22) to mitigate microglial activation and alleviate depression-like behaviors in male mice.

  PMID:41922794 2026 Mol Psychiatry

  Microglia-neuron contacts have been shown to regulate neural network activity through the formation and elimination of synapses. The pathogenesis of major depressive disorder is accompanied by a decline in brain-derived neurotrophic factor (BDNF) signaling, associated with increased microglia activity that disrupts cognitive function. The actions of both typical and rapid-acting antidepressant drugs, which have been shown to increase BDNF signaling through the tropomyosin receptor kinase B (TrkB) receptor, decrease microglia activation and the levels of pro-inflammatory cytokines. Examining the link between BDNF signaling and the microglial pro-inflammatory response, we demonstrate that TrkB signaling elicits the neuronal secretion of CD22 (Siglec-2), a sialic acid-binding immunoglobulin-type lectin, to inhibit microglial activation and alleviate depression-like symptoms. In a male chronic mild stress (CMS) mouse model of depression decreased expression of the postsynaptic scaffolding

• Antidepressant Effects of Combined Eucommia-Gastrodia Extract via Modulation of the HIF-1α-EPO/cAMP-CREB-BDNF Pathway: An Integrated Network Pharmacology and In Vivo Study.

  PMID:41921863 2026 Brain Res Bull

  OBJECTIVE: This study aims to elucidate the pharmacological basis and antidepressant mechanisms of a combined extract from Eucommia ulmoides Oliv. And Gastrodia elata Bl. (Eucommia-Gastrodia extract), employing an integrated strategy that combines UHPLC-QTOF-MS analysis, network pharmacology, molecular docking, and in vivo validation. METHODOLOGY: This research integrated computational approaches network pharmacology, molecular docking and in vivo experimental investigations. Initially, the active constituents of the EGE were identified through ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS). Potential targets related to depression were predicted using the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and SwissADME. Protein-protein interaction (PPI) networks were constructed via the STRING database, followed by the development of a comprehensive "drug-active ingredient-target-disease" network. Fu

• The Potential Functions and Beneficial Effects of Melatonin on Cognitive Impairment, Neuroinflammation, Blood-Brain Barrier Leakage, and Synaptic Dysfunction in the Offspring of Mice Exposed to Gestational Intermittent Hypoxia.

  PMID:41917799 2026 Brain Behav

  INTRODUCTION: Gestational intermittent hypoxia (GIH), which serves as a model for obstructive sleep apnea (OSA), is associated with adverse maternal and neonatal outcomes, especially cognitive impairments in offspring. Growing evidence supports that the anti-inflammatory actions of melatonin significantly influence the peripartum environment and contribute to the mitigation of neurodegeneration. However, the full impact of GIH on offspring cognition and the molecular mechanisms by which melatonin modulates these effects remain uncertain. Thus, in this study, we explored the neurobiological changes in GIH-exposed offspring and the mechanism underlying maternal melatonin supplementation in preventing these alterations using a murine model. METHODS: C57BL/6J mice were exposed to GIH between gestational Days 15 and 21. Concurrently, dams received either vehicle or melatonin. The Morris water maze test was employed to evaluate offspring cognitive function, after which the offspring were eut

• AICAR improves depression-like behaviors and is associated with hippocampal AMPK activation and modulation of neurogenesis and neuroinflammation in a microbiota disruption model.

  PMID:41932583 2026 Neurochem Int

• Complementary mechanisms of high-carbohydrate diets and ketogenic diets restore adult hippocampal neurogenesis and cognitive function in high-fat diet induced obesity in mice.

  PMID:41475465 2026 J Nutr Biochem

• Experts' narrative review "Mastication, Hippocampal Structure Changes and Cognition".

  PMID:41576846 2026 Arch Oral Biol

• Dysregulation of Drp1 and Mfn2 is associated with reduced PSD-95, synaptophysin, and BDNF expression in a rat model of Alzheimer's disease.

  PMID:41932483 2026 Int J Biol Macromol

• Epigenetic mechanisms and therapeutic innovations in chronic pain-associated neuropsychiatric co-morbidities.

  PMID:41554641 2026 Br J Pharmacol

• Biomarkers for Alzheimer's disease across diverse biological domains: an umbrella review and evidence map.

  PMID:40680830 2026 J Adv Res

• Postbiotics and the gut-brain axis: A mechanistic review on modulating neuroinflammation and cognitive aging.

  PMID:41570486 2026 J Neuroimmunol

• Nanotherapeutic potential of Baicalein-encapsulated hUC-MSC exosomes in Alzheimer's disease: Modulating oxidative stress and neuroinflammation.

  PMID:41370943 2026 Biomater Adv

• miRNA-206 in muscle and central nervous system crosstalk during exercise: A double-edged sword with therapeutic potential.

  PMID:41571168 2026 Neurosci Biobehav Rev

• Integrative GWAS identifies novel loci and genetic links between psychiatric and metabolic factors in anorexia nervosa.

  PMID:41927769 2026 Mol Psychiatry

• Zhi-Gan Formula improved insomnia and anxiety comorbidity in a mouse model via PACAP signaling in the medial prefrontal cortex.

  PMID:41525914 2026 J Ethnopharmacol

• Single transient exposure to low-frequency low-intensity electrical stimulation produces ketamine-like effects in human iPSC-derived dopaminergic neurons via Ca2(+)-dependent BDNF and mTOR signaling.

  PMID:41942002 2026 Neuropharmacology

• Triterpenoid saponins from Platycodon grandiflorus exhibit antidepressant-like effects and are associated with BDNF-mediated neuroplasticity signaling in a chronic stress model.

  PMID:41539634 2026 J Ethnopharmacol

• Nanopiezoelectric 3D-Bioprinted Neural Organoid Models Epileptic Neuron-Microglia Circuit in Neurodegeneration.

  PMID:41877549 2026 Nano Lett

• Designed Liquid Crystalline Nanoassemblies From Clinically Validated Polyunsaturated Lipids for Combined Antioxidant, Anti-Apoptotic, and Neurotrophic Treatments.

  PMID:41937329 2026 Adv Healthc Mater

• Serpina1e mediates the exercise-induced enhancement of hippocampal memory in male mice

  PMID:41957371 2026 Nat Commun

• Ubiquinol Ameliorates Social Disruption-induced Behavioral Changes via Modulating Inflammatory Responses and PPARα Activation

  PMID:41962635 2026 Behav Brain Res

• Dietary Advanced Glycation End Products Induced Anxiety- and Depression-like Behaviors in Female C57BL/6 Mice and the Ameliorative Effects of Quercetin

  PMID:41962780 2026 J Nutr Biochem

• BDNF Protects Against Neuronal Damage Induced by TNF and β-Amyloid Peptides by Targeting JNK Activation

  PMID:41964857 2026 Neurochem Res

Evidence against (19)

• Adult neurogenesis contribution to human cognition remains controversial

  PMID:35503338 2022 Zool Res

  Adult neurogenesis is the creation of new neurons which integrate into the existing neural circuit of the adult brain. Recent evidence suggests that adult hippocampal neurogenesis (AHN) persists throughout life in mammals, including humans. These newborn neurons have been implicated to have a crucial role in brain functions such as learning and memory. Importantly, studies have also found that hippocampal neurogenesis is impaired in neurodegenerative and neuropsychiatric diseases. Alzheimer's disease (AD) is one of the most common forms of dementia affecting millions of people. Cognitive dysfunction is a common symptom of AD patients and progressive memory loss has been attributed to the degeneration of the hippocampus. Therefore, there has been growing interest in identifying how hippocampal neurogenesis is affected in AD. However, the link between cognitive decline and changes in hippocampal neurogenesis in AD is poorly understood. In this review, we summarized the recent literature

• BDNF delivery to CNS faces significant pharmacokinetic challenges

  PMID:36211804 2022 Tremor Other Hyperkinet Mov (N Y)

  BACKGROUND: Tremor is one of the most prevalent symptoms in Parkinson's Disease (PD). The progression and management of tremor in PD can be challenging, as response to dopaminergic agents might be relatively poor, particularly in patients with tremor-dominant PD compared to the akinetic/rigid subtype. In this review, we aim to highlight recent advances in the underlying pathogenesis and treatment modalities for tremor in PD. METHODS: A structured literature search through Embase was conducted using the terms "Parkinson's Disease" AND "tremor" OR "etiology" OR "management" OR "drug resistance" OR "therapy" OR "rehabilitation" OR "surgery." After initial screening, eligible articles were selected with a focus on published literature in the last 10 years. DISCUSSION: The underlying pathophysiology of tremor in PD remains complex and incompletely understood. Neurodegeneration of dopaminergic neurons in the retrorubral area, in addition to high-power neural oscillations in the cerebello-tha

• Microneedle-mediated nose-to-brain drug delivery for improved Alzheimer's disease treatment

  PMID:38219911 2024 J Control Release

  Conventional transnasal brain-targeted drug delivery strategies are limited by nasal cilia clearance and the nasal mucosal barrier. To address this challenge, we designed dissolving microneedles combined with nanocarriers for enhanced nose-to-brain drug delivery. To facilitate transnasal administration, a toothbrush-like microneedle patch was fabricated with hyaluronic acid-formed microneedles and tannic acid-crosslinked gelatin as the base, which completely dissolved in the nasal mucosa within seconds leaving only the base, thereby releasing the loaded cyclodextrin-based metal-organic frameworks (CD-MOFs) without affecting the nasal cilia and nasal microbial communities. As nanocarriers for high loading of huperzine A, these potassium-structured CD-MOFs, reinforced with stigmasterol and functionalized with lactoferrin, possessed improved physical stability and excellent biocompatibility, enabling efficient brain-targeted drug delivery. This delivery system substantially attenuated H2O

• Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer.

  PMID:33096634 2020 Int J Mol Sci

  Brain-derived neurotrophic factor (BDNF) is one of the most distributed and extensively studied neurotrophins in the mammalian brain. BDNF signals through the tropomycin receptor kinase B (TrkB) and the low affinity p75 neurotrophin receptor (p75NTR). BDNF plays an important role in proper growth, development, and plasticity of glutamatergic and GABAergic synapses and through modulation of neuronal differentiation, it influences serotonergic and dopaminergic neurotransmission. BDNF acts as paracrine and autocrine factor, on both pre-synaptic and post-synaptic target sites. It is crucial in the transformation of synaptic activity into long-term synaptic memories. BDNF is considered an instructive mediator of functional and structural plasticity in the central nervous system (CNS), influencing dendritic spines and, at least in the hippocampus, the adult neurogenesis. Changes in the rate of adult neurogenesis and in spine density can influence several forms of learning and memory and can

• Exercise therapy to prevent and treat Alzheimer's disease.

  PMID:37600508 2023 Front Aging Neurosci

  Alzheimer's disease (AD) is a progressive neurodegenerative disease in the elderly with dementia, memory loss, and severe cognitive impairment that imposes high medical costs on individuals. The causes of AD include increased deposition of amyloid beta (Aβ) and phosphorylated tau, age, mitochondrial defects, increased neuroinflammation, decreased synaptic connections, and decreased nerve growth factors (NGF). While in animals moderate-intensity exercise restores hippocampal and amygdala memory through increased levels of p-AKT, p-TrkB, and p-PKC and decreased levels of Aβ, tau phosphorylation, and amyloid precursor proteins (APP) in AD. Aerobic exercise (with an intensity of 50-75% of VO2 max) prevents hippocampal volume reduction, spatial memory reduction, and learning reduction through increasing synaptic flexibility. Exercise training induces the binding of brain-derived neurotrophic factor (BDNF) to TrkB and the binding of NGF to TrkA to induce cell survival and neuronal plasticity

• Brain-derived neurotrophic factor in Alzheimer's disease and its pharmaceutical potential.

  PMID:35090576 2022 Transl Neurodegener

  Synaptic abnormalities are a cardinal feature of Alzheimer's disease (AD) that are known to arise as the disease progresses. A growing body of evidence suggests that pathological alterations to neuronal circuits and synapses may provide a mechanistic link between amyloid β (Aβ) and tau pathology and thus may serve as an obligatory relay of the cognitive impairment in AD. Brain-derived neurotrophic factors (BDNFs) play an important role in maintaining synaptic plasticity in learning and memory. Considering AD as a synaptic disorder, BDNF has attracted increasing attention as a potential diagnostic biomarker and a therapeutical molecule for AD. Although depletion of BDNF has been linked with Aβ accumulation, tau phosphorylation, neuroinflammation and neuronal apoptosis, the exact mechanisms underlying the effect of impaired BDNF signaling on AD are still unknown. Here, we present an overview of how BDNF genomic structure is connected to factors that regulate BDNF signaling. We then discu

• Neurogenesis in the Adult and Aging Brain.

  PMID:21204350 2007

  Given that neurogenesis is regionally restricted in the adult brain, the direct contribution of changes in neurogenesis to the development of aging-related cognitive decline is likely limited, perhaps accounting for the difficulty thus far in linking the decline in neurogenesis to specific neural deficits. As investigations of the contributions of adult neurogenesis to neural function continue, however, it is reasonable to expect they will demonstrate that the aging-related loss of the plasticit

• Age-dependent regenerative mechanisms in the brain.

  PMID:39584473 2024 Biochem Soc Trans

  Repairing the adult mammalian brain represents one of the greatest clinical challenges in medicine. Injury to the adult brain often results in substantial loss of neural tissue and permanent functional impairment. In contrast with the adult, during development, the mammalian brain exhibits a remarkable capacity to replace lost cells. A plethora of cell-intrinsic and extrinsic factors regulate the age-dependent loss of regenerative potential in the brain. As the developmental window closes, neural stem cells undergo epigenetic changes, limiting their proliferation and differentiation capacities, whereas, changes in the brain microenvironment pose additional challenges opposing regeneration, including inflammation and gliosis. Therefore, studying the regenerative mechanisms during development and identifying what impairs them with age may provide key insights into how to stimulate regeneration in the brain. Here, we will discuss how the mammalian brain engages regenerative mechanisms upo

• EphA4 Targeting Peptide-Conjugated Extracellular Vesicles Rejuvenates Adult Neural Stem Cells and Exerts Therapeutic Benefits in Aging Rats.

  PMID:39288278 2024 ACS Chem Neurosci

  Aging and various neurodegenerative diseases cause significant reduction in adult neurogenesis and simultaneous increase in quiescent neural stem cells (NSCs), which impact the brain's regenerative capabilities. To deal with this challenging issue, current treatments involve stem cell transplants or prevention of neurodegeneration; however, the efficacy or success of this process remains limited. Therefore, extensive and focused investigation is highly demanding to overcome this challenging task. Here, we have designed an efficient peptide-based EphA4 receptor-targeted ligand through an in silico approach. Further, this strategy involves chemical conjugation of the peptide with adipose tissue stem cell-derived EV (Exo-pep-11). Interestingly, our newly designed engineered EV, Exo-pep-11, targets NSC through EphA4 receptors, which offers promising therapeutic advantages by stimulating NSC proliferation and subsequent differentiation. Our result demonstrates that NSC successfully internal

• Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders.

  PMID:28670349 2017 Clin Epigenetics

  Ageing is the main risk factor for human neurological disorders. Among the diverse molecular pathways that govern ageing, epigenetics can guide age-associated decline in part by regulating gene expression and also through the modulation of genomic instability and high-order chromatin architecture. Epigenetic mechanisms are involved in the regulation of neural differentiation as well as in functional processes related to memory consolidation, learning or cognition during healthy lifespan. On the other side of the coin, many neurodegenerative diseases are associated with epigenetic dysregulation. The reversible nature of epigenetic factors and, especially, their role as mediators between the genome and the environment make them exciting candidates as therapeutic targets. Rather than providing a broad description of the pathways epigenetically deregulated in human neurological disorders, in this review, we have focused on the potential use of epigenetic enzymes as druggable targets to ame

• Targeting the blood-brain barrier for the delivery of stroke therapies.

  PMID:33497734 2021 Adv Drug Deliv Rev

  A variety of neuroprotectants have shown promise in treating ischemic stroke, yet their delivery to the brain remains a challenge. The endothelial cells lining the blood-brain barrier (BBB) are emerging as a dynamic factor in the response to neurological injury and disease, and the endothelial-neuronal matrix coupling is fundamentally neuroprotective. In this review, we discuss approaches that target the endothelium for drug delivery both across the BBB and to the BBB as a viable strategy to facilitate neuroprotective effects, using the example of brain-derived neurotrophic factor (BDNF). We highlight the advances in cell-derived extracellular vesicles (EVs) used for CNS targeting and drug delivery. We also discuss the potential of engineered EVs as a potent strategy to deliver BDNF or other drug candidates to the ischemic brain, particularly when coupled with internal components like mitochondria that may increase cellular energetics in injured endothelial cells.

• Therapeutic Potential of Natural Compounds for Brain Ischemia-Reperfusion Injury.

  PMID:41007298 2025 Biology (Basel)

  Brain ischemia-reperfusion (I/R) injury, commonly occurring in ischemic stroke and post-cardiac arrest scenarios, results in complex secondary damage involving oxidative stress, inflammation, apoptosis, and blood-brain barrier (BBB) breakdown. Despite decades of research, no pharmacological agent has yet been clinically approved for post-I/R neuroprotection. Natural compounds have recently gained attention for their multimodal therapeutic potential, including antioxidant, anti-inflammatory, anti-apoptotic, and neuroregenerative effects. This review highlights nine promising candidates-resveratrol, curcumin, quercetin, berberine, ginkgolide B, baicalin, naringin, fucoidan, and astaxanthin-that exhibit efficacy in experimental models of I/R injury when administered after the insult. Their chemical structures, pharmacokinetics, and mechanisms of action are described in detail, focusing on key signaling pathways such as nuclear factor erythroid 2-related (Nrf2), nuclear factor kappa B (NF-

• Murine model of minimally invasive nasal depot (MIND) technique for central nervous system delivery of blood-brain barrier-impermeant therapeutics.

  PMID:39548349 2024 Lab Anim (NY)

  The blood-brain barrier (BBB) poses a substantial obstacle to the successful delivery of therapeutics to the central nervous system (CNS). The transnasal route has been extensively explored, but success rates have been modest due to challenges related to the precise anatomical placement of drugs, the small volumes that the olfactory cleft can accommodate and short drug residence times due to mucociliary clearance. Here, to address these issues, we have developed a surgical technique known as the minimally invasive nasal depot (MIND), which allows the accurate placement of depot drugs into the submucosal space of the olfactory epithelium of rats. This technique exploits the unique anatomy of the olfactory apparatus to enable transnasal delivery of drugs into the CNS, bypassing the BBB. In our rat model, a bony window is created in the animal snout to expose the submucosal space. Using the MIND technique, we have successfully delivered oligonucleotides to the CNS in Sprague-Dawley and Lo

• Overexpression of BDNF by Astrocytes Targeted Delivery of mRNA Ameliorates Cognitive Impairment in Mouse Model of TBI.

  PMID:40903436 2025 ACS Chem Neurosci

  Brain-derived neurotrophic factor (BDNF) plays an important role in synaptic development and plasticity. It is a promising therapeutic target for improving neurofunctional outcomes after traumatic brain injury (TBI). However, the delivery of BDNF faces several significant challenges including limited entry into the CNS due to blood-brain barrier (BBB), short half-life, and potential side effects. The use of viral vectors like AAV to deliver the BDNF gene directly to the brain has shown promise in animal models. However, issues with host immunogenicity and limited biodistribution remain. Herein, we report a successful restoration of cognitive function of a TBI mouse model by efficient delivery of BDNF mRNA loaded to a novel lipid nanoparticle (DA6 LNP). DA6 LNPs loaded with either luciferase mRNA or GFP mRNA were internalized by astrocytes and dose dependently expressed the corresponding protein. Two consecutive intravenous injections of DA6 LNPs loaded with BDNF mRNA to a TBI mouse mod

• Behavioral and psychological symptoms of dementia (BPSD) and impaired cognition reflect unsuccessful neuronal compensation in the pre-plaque stage and serve as early markers for Alzheimer's disease in the APP23 mouse model.

  PMID:29572105 2018 Behav Brain Res

  Recent research on Alzheimer's disease (AD) focuses on processes prior to amyloid-beta plaque deposition accounting for the progress of the disease. However, early mechanisms of AD are still poorly understood and predictors of the disease in the pre-plaque stage essential for initiating an early therapy are lacking. Behavioral and psychological symptoms of dementia (BPSD) and potentially impaired cognition may serve as predictors and early clinical diagnostic markers for AD. To investigate potential BPSD and cognitive impairments in association with neuronal cell development as such markers for AD in the pre-plaque stage, female APP23 mice at eight, 19 and 31 weeks of age and corresponding control animals were tested for BPSD (elevated zero maze; sucrose preference test), motor coordination (rotarod), spatial memory and reversal learning (Morris water maze) and hippocampal neurogenesis as a neuronal correlate for hippocampus-dependent behavior. To evaluate a potential therapeutic effec

• Advances and Therapeutic Potential of Anthraquinone Compounds in Neurodegenerative Diseases: A Comprehensive Review.

  PMID:41868184 2026 Drug Des Devel Ther

  BACKGROUND: Rhubarb, traditionally used in China for neurological disorders, has recently attracted considerable scientific attention for its neuroprotective and cerebrovascular benefits. The main therapeutic components of rhubarb are anthraquinones, including emodin, aloe-emodin, chrysophanol, rhein, and physcion. Accumulating experimental evidence indicates that anthraquinones are of importance in neurodegenerative diseases (NDDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. However, as a promising candidate for drug development, the mechanisms by which anthraquinones treat NDDs have not been systematically reviewed. Therefore, this article outlines the anti-neurodegenerative effects of anthraquinones, focusing on their molecular mechanisms. OBJECTIVE: This article reviews recent research progress of anthraquinones in NDDs, focusing on their potential targets and pathways to provide new ideas for the intervention and treatment of ND

• Human umbilical cord mesenchymal stem cells therapy for Alzheimer's disease: a systematic review and meta-analysis of mouse models.

  PMID:41847685 2026 Front Neurol

  OBJECTIVE: Given the limitations of current treatments for Alzheimer's disease (AD), this study aims to comprehensively evaluate the therapeutic efficacy of human umbilical cord mesenchymal stem cells (hUCMSCs) in AD mouse models through a systematic review and meta-analysis. Additionally, we explore the impact of transplantation dose and route on treatment outcomes to identify the optimal window for clinical application. METHODS: In accordance with the PRISMA guidelines, we systematically searched four major databases to identify randomized controlled trials involving hUCMSCs in AD mouse models. We used the standardized mean difference (SMD) to synthesize effect sizes and performed subgroup analyses based on pre-defined transplantation routes and doses. RESULTS: A total of 13 studies were included in the analysis. The meta-analysis revealed that hUCMSCs transplantation significantly improved spatial learning and memory in AD model mice, with a marked reduction in escape latency (SMD =

• Modulation of mitochondrial quality by exercise mimetics: A potential strategy for the prevention and treatment of Alzheimer's disease.

  PMID:41804756 2026 J Alzheimers Dis

  Decline in mitochondrial quality is a prominent pathological feature of Alzheimer's disease (AD), manifested by impaired energy metabolism, disrupted mitochondrial biogenesis, abnormal mitochondrial dynamics, and defective mitophagy. Increasing evidence indicates that mitochondrial dysfunction contributes to the exacerbation of amyloid-β (Aβ) deposition and tau protein hyperphosphorylation, thereby accelerating AD pathogenesis. Of particular interest, physical exercise has been shown to effectively enhance mitochondrial quality and help prevent or slow the progression of AD, largely through the activation of key signaling pathways such as adenosine monophosphate-activated protein kinase (AMPK) and sirtuin 1 (SIRT1). However, regular physical activity may not be feasible for individuals in the prodromal or clinical stages of AD. In this context, exercise mimetics-compounds that pharmacologically simulate the molecular effects of exercise-have emerged as a promising alternative intervent

• Plant-derived bioactive compounds modulate the gut microbiota in Alzheimer's disease: Metabolite signaling, neuroimmune circuits, and systems-level regulation.

  PMID:41678917 2026 Phytomedicine

Evidence matrix

Top-ranked evidence

Bayesian persona consensus

Cite this hypothesis

@misc{scidex_hypothesis_hvar9c03,
  title        = {Hippocampal CA3-CA1 synaptic rescue via DHHC2-mediated PSD95 palmitoylation sta…},
  author       = {etl-backfill},
  year         = {2026},
  howpublished = {SciDEX hypothesis},
  url          = {https://prism.scidex.ai/hypotheses/h-var-9c0368bb70},
  note         = {SciDEX artifact hypothesis:h-var-9c0368bb70}
}