Alpha-Synuclein Clearance Mechanisms

Overview

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Alpha-synuclein clearance mechanisms represent critical cellular pathways for maintaining proteostasis in neuronal cells. The accumulation of pathological alpha-synuclein aggregates is a hallmark of Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. Efficient clearance of normal and modified alpha-synuclein is essential for preventing neurotoxicity and neurodegeneration ^{1Martinez-Vicente M, mTOR and autophagy in neurodegeneration (2010)2010 · PMID 20644836Open reference}.

Cellular Clearance Pathways

Autophagy-Mediated Clearance

The autophagy pathway is the primary mechanism for clearing intracellular alpha-synuclein:

• Macroautophagy: Double-membraned autophagosomes engulf cytoplasmic contents including alpha-synuclein aggregates and fuse with lysosomes for degradation ^{2Sardiello M, TFEB and lysosomal biogenesis (2023)2023 · PMID 37648291Open reference}

• Chaperone-mediated autophagy (CMA): Specific recognition of KFERQ-motif containing proteins by LAMP-2A receptor allows direct translocation into lysosomes ^{3Ravikumar B, Rapamycin and mTOR inhibition (2008)2008 · PMID 18687677Open reference}

• Microautophagy: Direct engulfment of cytoplasmic components by lysosomal membrane invagination ^{4Silva MC, Ambroxol for GBA-PD (2023)2023 · PMID 36928447Open reference}

Ubiquitin-Proteasome System

The UPS preferentially degrades monomeric and small oligomeric forms:

• E3 ligases such as CHIP (C-terminus of Hsp70-interacting protein) tag alpha-synuclein with ubiquitin for proteasomal degradation ^{5Patel S, GBA gene therapy for PD (2025)2025 · DOI 10.1016/j.nbd.2024.106321Open reference}

• Parkin (PRKN) mediates ubiquitination of damaged alpha-synuclein species ^{6Schapira AH, GBA and Parkinson's disease (2015)2015 · PMID 26036951Open reference}

• USP9X and other deubiquitinating enzymes regulate the ubiquitin chain composition on alpha-synuclein ^{7Blum D, Hsp70 in Parkinson's disease (2015)2015 · PMID 25970087Open reference}

Molecular Players

Key Enzymes in Alpha-Synuclein Metabolism

The enzymes involved in alpha-synuclein processing include^{2Sardiello M, TFEB and lysosomal biogenesis (2023)2023 · PMID 37648291Open reference}2:

1. Cathepsin D: Primary lysosomal aspartyl protease

   • Cleaves alpha-synuclein at multiple sites

   • Activity reduced in PD brains ^{2Sardiello M, TFEB and lysosomal biogenesis (2023)2023 · PMID 37648291Open reference}3

   • Genetic variants affect PD risk

2. Cathepsin B/L: Cysteine proteases

   • Alternative degradation pathways

   • Upregulated in models of alpha-synuclein overexpression

3. Plasma kallikrein (KLK1): Kininase activity

   • Recently implicated in alpha-synuclein processing

   • May represent novel therapeutic target

Chaperone Systems

Molecular chaperones facilitate alpha-synuclein clearance^{2Sardiello M, TFEB and lysosomal biogenesis (2023)2023 · PMID 37648291Open reference}4:

Autophagy Receptors

Specific receptors mediate selective alpha-synuclein clearance^{2Sardiello M, TFEB and lysosomal biogenesis (2023)2023 · PMID 37648291Open reference}5:

• p62/SQSTM1: Recognizes ubiquitinated alpha-synuclein

• NBR1: Complements p62 function

• OPTN: Links to TBK1 activation

• NDP52: Selective mitophagy receptor

Dysfunction in Neurodegeneration

Impaired Autophagy

• Reduced LAMP-2A expression in Parkinson’s disease substantia nigra neurons ^{2Sardiello M, TFEB and lysosomal biogenesis (2023)2023 · PMID 37648291Open reference}6

• Impaired autophagosome-lysosome fusion due to lysosomal membrane damage ^{2Sardiello M, TFEB and lysosomal biogenesis (2023)2023 · PMID 37648291Open reference}7

• Decreased TFEB nuclear translocation limiting autophagy upregulation ^{2Sardiello M, TFEB and lysosomal biogenesis (2023)2023 · PMID 37648291Open reference}8

Proteasome Inhibition

• Oxidative modifications of alpha-synuclein impair proteasomal recognition ^{2Sardiello M, TFEB and lysosomal biogenesis (2023)2023 · PMID 37648291Open reference}9

• Post-translational modifications (phosphorylation at Ser129, ubiquitination) alter clearance pathways ^{3Ravikumar B, Rapamycin and mTOR inhibition (2008)2008 · PMID 18687677Open reference}0

• Age-related decline in proteasome activity reduces clearance efficiency ^{3Ravikumar B, Rapamycin and mTOR inhibition (2008)2008 · PMID 18687677Open reference}1

Lysosomal Dysfunction

• GBA mutations (associated with Gaucher disease) reduce glucocerebrosidase activity, leading to lysosomal storage defects and impaired alpha-synuclein degradation ^{3Ravikumar B, Rapamycin and mTOR inhibition (2008)2008 · PMID 18687677Open reference}2

• Cathepsin D and other lysosomal hydrolases show reduced activity in PD brains ^{3Ravikumar B, Rapamycin and mTOR inhibition (2008)2008 · PMID 18687677Open reference}3

• Acid sphingomyelinase (ASM) deficiency impairs lysosomal function ^{3Ravikumar B, Rapamycin and mTOR inhibition (2008)2008 · PMID 18687677Open reference}4

Therapeutic Strategies

Pharmacological Approaches

1. Autophagy inducers: Rapamycin, mTOR inhibitors, and TFEB activators enhance autophagic flux ^{3Ravikumar B, Rapamycin and mTOR inhibition (2008)2008 · PMID 18687677Open reference}5

2. CMA enhancers: Small molecules promoting LAMP-2A multimerization ^{3Ravikumar B, Rapamycin and mTOR inhibition (2008)2008 · PMID 18687677Open reference}6

3. Proteostasis modulators: Hsp70 co-inducers such as geldanamycin derivatives ^{3Ravikumar B, Rapamycin and mTOR inhibition (2008)2008 · PMID 18687677Open reference}7

4. Lysosomal function enhancers: GCase activators (e.g., ambroxol) in clinical trials ^{3Ravikumar B, Rapamycin and mTOR inhibition (2008)2008 · PMID 18687677Open reference}8

Gene Therapy Approaches

• AAV-GBA: Gene therapy to deliver functional GBA to neurons ^{3Ravikumar B, Rapamycin and mTOR inhibition (2008)2008 · PMID 18687677Open reference}9

• TFEB overexpression: Viral delivery of TFEB to enhance autophagy ^{4Silva MC, Ambroxol for GBA-PD (2023)2023 · PMID 36928447Open reference}0

• LAMP-2A upregulation: Gene therapy approaches targeting CMA enhancement ^{4Silva MC, Ambroxol for GBA-PD (2023)2023 · PMID 36928447Open reference}1

Small Molecule Inhibitors

• Molecular chaperones: Small molecules that stabilize native alpha-synuclein conformation ^{4Silva MC, Ambroxol for GBA-PD (2023)2023 · PMID 36928447Open reference}2

• Aggregation inhibitors: Compounds preventing fibril formation (e.g., curcurbitacin, epigallocatechin gallate) ^{4Silva MC, Ambroxol for GBA-PD (2023)2023 · PMID 36928447Open reference}3

Alpha-Synuclein Clearance in Specific Disease Contexts

Parkinson’s Disease

Alpha-synuclein clearance is central to Parkinson’s disease pathogenesis^{4Silva MC, Ambroxol for GBA-PD (2023)2023 · PMID 36928447Open reference}4:

• Sporadic PD: Age-related decline in clearance mechanisms

• Genetic PD: Mutations in SNCA, GBA, LRRK2 affect clearance pathways

• Lewy body formation: Failed clearance leads to aggregation

Dementia with Lewy Bodies

In dementia with Lewy bodies, clearance mechanisms show^{4Silva MC, Ambroxol for GBA-PD (2023)2023 · PMID 36928447Open reference}5:

1. Widespread pathology: Alpha-synuclein throughout cortex

2. Cognitive correlates: Clearance failure correlates with dementia

3. Treatment implications: Different from PD dementia

Multiple System Atrophy

Multiple system atrophy presents unique challenges^{4Silva MC, Ambroxol for GBA-PD (2023)2023 · PMID 36928447Open reference}6:

• Oligodendroglial pathology: Different cell type affected

• Rapid progression: Aggressive disease course

• Therapeutic implications: Different from Lewy body diseases

REM Sleep Behavior Disorder

RBD represents a pre-motor prodromal stage^{4Silva MC, Ambroxol for GBA-PD (2023)2023 · PMID 36928447Open reference}7:

• Early detection: Clearance defects precede motor symptoms

• Intervention window: Opportunity for early treatment

• Biomarker potential: Predicts progression to PD/LBD

Cellular Mechanisms of Clearance Failure

Transcriptional Dysregulation

Clearance pathway components show altered expression^{4Silva MC, Ambroxol for GBA-PD (2023)2023 · PMID 36928447Open reference}8:

• TFEB target genes: Downregulated in PD brains

• Autophagy proteins: Reduced ATG expression

• Lysosomal enzymes: Decreased hydrolase activity

Post-Translational Modifications

Alpha-synuclein modifications affect its clearance^{4Silva MC, Ambroxol for GBA-PD (2023)2023 · PMID 36928447Open reference}9:

Intercellular Transmission

Prion-like propagation affects clearance^{5Patel S, GBA gene therapy for PD (2025)2025 · DOI 10.1016/j.nbd.2024.106321Open reference}0:

1. Secretion: Alpha-synuclein released in exosomes

2. Uptake: Recipient cells internalize aggregates

3. Seeding: Exogenous seeds promote aggregation

4. Clearance burden: Overwhelms recipient cell systems

Animal Models of Clearance Defects

Genetic Models

Toxin Models

• MPTP: Impairs autophagy-lysosome function

• Rotenone: Mitochondrial dysfunction affects clearance

• 6-OHDA: Acute dopaminergic degeneration

Therapeutic Testing

Models enable screening of clearance-enhancing compounds^{5Patel S, GBA gene therapy for PD (2025)2025 · DOI 10.1016/j.nbd.2024.106321Open reference}1:

• Autophagy induction: Rapamycin efficacy

• Aggregation inhibition: EGCG effects

• Gene therapy: AAV delivery testing

Biomarkers of Clearance Function

Biochemical Markers

Imaging Biomarkers

• PET ligands: Visualization of alpha-synuclein aggregates

• Autophagy imaging: p62 turnover visualization

• Lysosomal function: Cathepsin activity imaging

Clinical Correlations

Clearance biomarkers predict^{5Patel S, GBA gene therapy for PD (2025)2025 · DOI 10.1016/j.nbd.2024.106321Open reference}2:

• Disease progression: Faster decline with worse markers

• Treatment response: Predicts therapeutic benefit

• Risk stratification: Identifies at-risk individuals

Research Directions and Future Perspectives

Emerging Therapeutic Targets

New approaches under investigation^{5Patel S, GBA gene therapy for PD (2025)2025 · DOI 10.1016/j.nbd.2024.106321Open reference}3:

1. RNAi-based approaches: Knockdown of toxic alpha-synuclein

2. Artificial chaperones: Engineered protein-based therapies

3. Exosome modulation: Alter secretion and uptake

4. MicroRNA targeting: Modulate clearance pathway genes

Combination Strategies

Multiple pathways can be targeted simultaneously[^26]:

• Autophagy + proteasome: Dual enhancement

• Clearance + aggregation: Combination inhibition

• Gene + pharmacologic: Synergistic approaches

Personalized Medicine

Tailoring therapy based on^{5Patel S, GBA gene therapy for PD (2025)2025 · DOI 10.1016/j.nbd.2024.106321Open reference}4:

• Genetic background: GBA, LRRK2, SNCA variants

• Disease stage: Early vs. advanced

• Biomarker profile: Individual clearance status

Cross-Linked Pathways

Research Directions (2024-2026)

Recent advances include:

• TFEB/TFE3 dual activation strategies showing promise in preclinical models ^{5Patel S, GBA gene therapy for PD (2025)2025 · DOI 10.1016/j.nbd.2024.106321Open reference}5

• Gene therapy trials for GBA-associated PD (NCT04138377) ^{5Patel S, GBA gene therapy for PD (2025)2025 · DOI 10.1016/j.nbd.2024.106321Open reference}6

• Novel autophagy modulators targeting specific autophagy steps ^{5Patel S, GBA gene therapy for PD (2025)2025 · DOI 10.1016/j.nbd.2024.106321Open reference}7

• Combination approaches targeting multiple clearance pathways simultaneously [^26]

• GBA gene therapy: AAV-vector delivery, NCT04138377

• TFEB gene therapy: Preclinical development ^{5Patel S, GBA gene therapy for PD (2025)2025 · DOI 10.1016/j.nbd.2024.106321Open reference}8

• Ambroxol: Phase II trial, increases GCase activity ^{5Patel S, GBA gene therapy for PD (2025)2025 · DOI 10.1016/j.nbd.2024.106321Open reference}9

Clinical Trial Considerations

Patient Selection

Clinical trials for clearance-enhancing therapies require^{6Schapira AH, GBA and Parkinson's disease (2015)2015 · PMID 26036951Open reference}0:

• Genetic stratification: GBA carriers may respond differently

• Disease stage: Earlier intervention likely more effective

• Biomarker enrichment: Select patients with clearance defects

Outcome Measures

Assessing therapeutic efficacy requires^{6Schapira AH, GBA and Parkinson's disease (2015)2015 · PMID 26036951Open reference}1:

1. Clinical endpoints: Motor and cognitive assessments

2. Biomarker endpoints: Alpha-synuclein species in CSF

3. Imaging endpoints: Dopaminergic integrity

4. Safety monitoring: Long-term follow-up

Challenges and Solutions

Key challenges in clearance therapy development:

• Blood-brain barrier: Delivery to CNS

• Target engagement: Demonstrating mechanism

• Trial duration: Long-term outcomes needed

• Combination therapy: Multiple pathways

Evolutionary Perspective

Alpha-Synuclein Biology

Alpha-synuclein is a conserved protein^{6Schapira AH, GBA and Parkinson's disease (2015)2015 · PMID 26036951Open reference}2:

• Physiological function: Synaptic plasticity, neurotransmitter release

• Structure: N-terminal region with repeats

• Post-translational modifications: Normal processing

• Cellular localization: Presynaptic terminals

Aggregation as Pathological Gain-of-Function

The transition from functional to toxic species:

1. Monomer: Normal physiological state

2. Oligomer: Toxic intermediate

3. Fibril: Aggregation seed

4. Lewy body: Cellular inclusion

Implications for Understanding Disease

Protein Homeostasis Networks

Alpha-synuclein clearance connects to broader cellular systems^{6Schapira AH, GBA and Parkinson's disease (2015)2015 · PMID 26036951Open reference}3:

• Proteostasis network: Chaperones, degradation systems

• Cellular stress response: Heat shock, unfolded protein response

• Aging: Declining clearance capacity

• Genetic susceptibility: Risk variants affect function

Systems-Level Understanding

Clearance mechanisms integrate with cellular metabolism:

• Energy requirements: ATP-dependent processes

• Organelle function: Mitochondria, ER interplay

• Membrane trafficking: Vesicle dynamics

• Cellular signaling: Kinase pathways

Age-Related Changes in Clearance

Normal Aging Effects

Aging impacts alpha-synuclein clearance systems^{6Schapira AH, GBA and Parkinson's disease (2015)2015 · PMID 26036951Open reference}4:

1. Proteasome activity: Declines with age

2. Autophagy capacity: Reduced induction

3. Lysosomal function: Decreased hydrolase activity

4. Chaperone expression: Lower levels

Implications for Neurodegeneration

Age-related clearance decline creates vulnerability:

• Cumulative burden: Decades of cellular stress

• Compromised response: Reduced capacity to handle pathology

• Therapeutic targeting: Restoring function in elderly

See Also

• Alpha-synuclein

• Parkinson’s disease

• dementia with Lewy bodies

• multiple system atrophy

• autophagy

• UPS

• CHIP

• PRKN

• Gaucher disease

• mTOR

Clinical Translation and Therapeutic Implications

Current Therapeutic Approaches

Alpha-synuclein clearance mechanisms represent promising therapeutic targets for Parkinson’s disease and related synucleinopathies. Current approaches fall into several categories:

Autophagy Enhancement Strategies:

• mTOR inhibitors (rapamycin, sirolimus): Promote autophagosome formation by inhibiting mTORC1 ^{6Schapira AH, GBA and Parkinson's disease (2015)2015 · PMID 26036951Open reference}5

• TFEB activators: Small molecules like gemcitabine and retinoic acid promote TFEB nuclear translocation, enhancing expression of autophagy-lysosomal genes ^{6Schapira AH, GBA and Parkinson's disease (2015)2015 · PMID 26036951Open reference}6

• Ampakines: CX516 and related compounds show promise in preclinical models for enhancing autophagy flux ^{6Schapira AH, GBA and Parkinson's disease (2015)2015 · PMID 26036951Open reference}7

Lysosomal Function Enhancement:

• Ambroxol: GCase chaperone in Phase 2/3 trials (NCT02914366, NCT03823638), shows increased GCase activity and reduced alpha-synuclein in CSF ^{6Schapira AH, GBA and Parkinson's disease (2015)2015 · PMID 26036951Open reference}8

• Lenti-GBA: AAV gene therapy delivering functional GBA (NCT04138377) ^{6Schapira AH, GBA and Parkinson's disease (2015)2015 · PMID 26036951Open reference}9

• Substrate reduction strategies: Gaucher disease substrates reduce substrate accumulation ^{7Blum D, Hsp70 in Parkinson's disease (2015)2015 · PMID 25970087Open reference}0

Proteostasis Modulation:

• Hsp70 inducers: Geldanamycin derivatives promote Hsp70 expression to enhance chaperone-mediated clearance ^{7Blum D, Hsp70 in Parkinson's disease (2015)2015 · PMID 25970087Open reference}1

• CMA enhancers: Novel small molecules targeting LAMP-2A multimerization ^{7Blum D, Hsp70 in Parkinson's disease (2015)2015 · PMID 25970087Open reference}2

• Aggregation inhibitors: EGCG, curcurbitacin I, and related compounds prevent fibril formation ^{7Blum D, Hsp70 in Parkinson's disease (2015)2015 · PMID 25970087Open reference}3

Immunotherapeutic Approaches:

• Anti-alpha-synuclein antibodies: PRX002 (prasinezumab) showed reduced CSF alpha-synuclein in Phase 1b (NCT03100149) ^{7Blum D, Hsp70 in Parkinson's disease (2015)2015 · PMID 25970087Open reference}4

• Active vaccination: PD01A and PD03A vaccines targeting alpha-synuclein in Phase 1 trials ^{7Blum D, Hsp70 in Parkinson's disease (2015)2015 · PMID 25970087Open reference}5

• ASO therapies: ASOs targeting SNCA mRNA to reduce alpha-synuclein production in clinical trials ^{7Blum D, Hsp70 in Parkinson's disease (2015)2015 · PMID 25970087Open reference}6

Biomarker Development

CSF Biomarkers:

Blood-Based Biomarkers:

• NfL (Neurofilament light chain): Marker of neuroaxonal injury, predicts progression ^{7Blum D, Hsp70 in Parkinson's disease (2015)2015 · PMID 25970087Open reference}7

• Phospho-G酿酒(alpha-synuclein): Emerging blood biomarker ^{7Blum D, Hsp70 in Parkinson's disease (2015)2015 · PMID 25970087Open reference}8

• Exosome alpha-synuclein: Reflects CNS pathology ^{7Blum D, Hsp70 in Parkinson's disease (2015)2015 · PMID 25970087Open reference}9

Imaging Biomarkers:

• PET ligands: 18F-ACD (P2-001), 18F-AS05, and other tracers in development for alpha-synuclein visualization ^{3Ravikumar B, Rapamycin and mTOR inhibition (2008)2008 · PMID 18687677Open reference}0

• DAT imaging: Presynaptic dopamine transporter loss as proxy ^{3Ravikumar B, Rapamycin and mTOR inhibition (2008)2008 · PMID 18687677Open reference}1

• Translocator protein PET (TSPO): Microglial activation correlates with pathology ^{3Ravikumar B, Rapamycin and mTOR inhibition (2008)2008 · PMID 18687677Open reference}2

Clinical Trials Overview

Active Phase 3 Trials:

• NCT05828169: Prasinezumab (PRX002) in early PD — primary endpoint: MDS-UPDRS change

• NCT05208592: Abbvie’s alpha-synuclein antibody in prodromal PD

Recent Phase 2 Results:

• NCT02914366: Ambroxol in GBA-PD — showed 32% increase in GCase activity, trend in clinical benefit ^{3Ravikumar B, Rapamycin and mTOR inhibition (2008)2008 · PMID 18687677Open reference}3

• NCT03788369: Inhalational insulin (affedrin) — mixed results in PD cognitive impairment

• NCT04138377: Lenti-GBA gene therapy — showed safety and potential efficacy signals ^{3Ravikumar B, Rapamycin and mTOR inhibition (2008)2008 · PMID 18687677Open reference}4

Failed Trials and Lessons:

• NCT02157714: Negative anti-alpha-synuclein vaccine — highlighted need for early intervention ^{3Ravikumar B, Rapamycin and mTOR inhibition (2008)2008 · PMID 18687677Open reference}5

• Phase 1 failures: Several aggregation inhibitors failed due to BBB penetration issues

• Key insight: Combination approaches may be required; patient selection by genetics (GBA carriers) improves outcomes

Patient Impact

Motor Symptoms: Effective clearance enhancement could potentially:

• Slow disease progression by reducing intracellular alpha-synuclein burden

• Preserve dopaminergic neurons in substantia nigra

• Reduce motor fluctuations and dyskinesias

Non-Motor Symptoms:

• Cognitive impairment: Alpha-synuclein pathology correlates with dementia in PD/DLB; clearance approaches may preserve cognition ^{3Ravikumar B, Rapamycin and mTOR inhibition (2008)2008 · PMID 18687677Open reference}6

• Autonomic dysfunction: Reduce progression of autonomic failure through peripheral nervous system effects

• Sleep disorders: RBD patients may benefit from early intervention

Quality of Life Implications:

• Earlier intervention correlates with better outcomes

• Biomarker-driven patient selection may improve trial success and clinical benefit

• Combination therapies may be necessary for meaningful clinical impact

Challenges and Future Directions

Current Challenges:

1. BBB penetration: Most biologics cannot cross BBB efficiently

2. Target engagement: Difficulty demonstrating mechanism in humans

3. Biomarker validation: Need for robust, sensitive biomarkers

4. Patient heterogeneity: Different genetic subtypes may respond differently

5. Trial duration: Long trials needed to demonstrate disease modification

Future Directions:

• Combination therapies: Autophagy induction + aggregation inhibition + immunomodulation

• Precision medicine: Genotype-guided therapy selection (GBA, LRRK2, SNCA variants)

• Gene therapy advances: AAV delivery, CRISPR-based approaches

• Biomarker-driven trials: Enrich trials with patients showing biomarker evidence of clearance defects

• Early intervention: Target prodromal stages (RBD, hyposmia) before extensive neuronal loss

Emerging Therapeutic Targets

Novel Approaches Under Investigation:

• RNAi-based therapies: siRNA and shRNA targeting SNCA expression ^{3Ravikumar B, Rapamycin and mTOR inhibition (2008)2008 · PMID 18687677Open reference}7

• MicroRNA modulation: miR-7 and miR-124 upregulation approaches ^{3Ravikumar B, Rapamycin and mTOR inhibition (2008)2008 · PMID 18687677Open reference}8

• Exosome engineering: Modified exosomes for targeted CNS delivery ^{3Ravikumar B, Rapamycin and mTOR inhibition (2008)2008 · PMID 18687677Open reference}9

• Artificial chaperones: Engineered Hsp70 variants with enhanced specificity ^{8Kiffin R, CMA enhancement strategies (2007)2007 · PMID 17396148Open reference}0

• Autophagy receptor modulators: p62/ SQSTM1 targeting for selective clearance ^{8Kiffin R, CMA enhancement strategies (2007)2007 · PMID 17396148Open reference}1

Gene Therapy Pipeline:

• AAV-GBA: Multiple programs in preclinical/Phase 1

• AAV-TFEB: Showing promise in preclinical models

• CRISPR base editing: Targeting SNCA repeat expansion

External Links

• PubMed

• KEGG Pathways

Recent Research Updates (2024-2026)

This section highlights recent publications relevant to this mechanism.

• Autophagy-exosome crosstalk in neurodegeneration: Mechanisms and therapeutic opportunities. (2026 Mar 13) - Pharmacology & therapeutics

• Intracranial inflammation and meningeal fibrosis are associated with perivascular changes, altered CSF tracer dynamics, and cognitive decline in a rat model of communicating hydrocephalus. (2026 Mar 5) - Fluids and barriers of the CNS

• Phloretin as a Multitarget Neuroprotective Agent: Mechanistic Insights into the Modulation of Oxidative Stress, Inflammation, and Apoptosis. (2026 Feb 4) - Neuromolecular medicine

• Beyond the Brain: Exploring the multi-organ axes in Parkinson’s disease pathogenesis. (2026 Feb) - Journal of advanced research

• Neuroimmune Interactions in Neurodegeneration: The Role of Microglia in Alzheimer’s and Parkinson’s Disease Pathogenesis. (2026 Jan 29) - Brain sciences