What question did this study set out to answer?

This review aims to evaluate how amyloid-β accumulation affects hippocampal synaptic plasticity and learning.

February 9, 2026Open Access

Molecular sabotage of hippocampal synaptic plasticity by amyloid-β in Alzheimer's disease: A narrative review

Puntos clave

This review aims to evaluate how amyloid-β accumulation affects hippocampal synaptic plasticity and learning.
Narrative review of existing literature on amyloid-β's impact on synaptic plasticity.
Critical evaluation of molecular mechanisms involved in cognitive decline due to amyloid-β.
Discussion of specific pathways such as glutamate receptor trafficking and neuroinflammation.
Amyloid-β disrupts glutamate receptor trafficking, leading to synaptic dysfunction.
Accumulation of tau and neuroinflammation are driven by amyloid-β, causing structural damage.
Overall, these mechanisms result in impaired learning and memory functions.

Resumen

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), Ca 2+ 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 Ca 2+ 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.

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Cite This Study

Behroozi et al. (Sun,) studied this question.

synapsesocial.com/papers/698979a6f0ec2af6756e772e https://doi.org/https://doi.org/10.1177/25424823261415807

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