Abstract
This narrative review aims to synthesize and critically evaluate the complex molecular mechanisms by which amyloid-β (Aβ) accumulation disrupts hippocampal synaptic plasticity, the cellular cornerstone of learning and memory in Alzheimer’s disease (AD). AD is characterized by progressive hippocampus-dependent cognitive decline, strongly linked to impaired synaptic plasticity, the cellular basis of learning and memory. This review deciphers how Aβ accumulation orchestrates synaptic sabotage in the hippocampus. We detail the core molecular machinery of hippocampal synaptic plasticity, emphasizing glutamate receptor trafficking (NMDAR/AMPAR), Ca2+ signaling, and neurotrophin pathways (BDNF/TrkB). Central to AD pathogenesis, soluble Aβ oligomers initiate synaptic dysfunction by targeting receptors like PrPᶜ/mGluR5, triggering NMDAR overactivation (via Fyn/NR2B) and AMPAR endocytosis. Aβ further drives tau hyperphosphorylation (via GSK-3β/CDK5), leading to dendritic p-tau accumulation and destabilization of the postsynaptic density (PSD). Concurrently, Aβ activates microglia (via TLR4/TREM2) and astrocytes, promoting neuroinflammation (IL-1β, TNF-α, C1q) and complement-mediated synaptic phagocytosis. Aβ-induced oxidative stress (ROS/RNS, lipid peroxidation) and mitochondrial failure (mPTP opening, energy depletion) exacerbate Ca2+ dyshomeostasis and plasticity impairment. Critically, Aβ disrupts BDNF/TrkB signaling, promoting proBDNF/p75ᴺᵀᴿ-mediated spine loss and inhibiting CREB-dependent plasticity gene expression. These converging pathways-glutamate receptor dysregulation, p-tau toxicity, neuroinflammation, oxidative stress, mitochondrial dysfunction, and neurotrophic collapse-culminate in synaptic apoptosis, profound structural damage (spine loss, PSD dissolution), and functional deficits (long-term potentiation (LTP) blockade, enhanced long-term depression (LTD)). This molecular cascade directly underlies hippocampal circuit failure and cognitive decline in AD. Future research must address Aβ strain specificity, regional vulnerability, glial metabolic coupling, resilience mechanisms, and novel therapeutic strategies targeting these pathways.