What does this research mean for the field?

Presynaptic accumulation of the amyloid precursor protein intermediate APP-CTFβ causes synaptic vesicle release defects and neuronal hyperexcitability, contributing to early synaptic dysfunction in Alzheimer's disease. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

To determine how the accumulation of amyloid precursor protein proteolytic fragments at excitatory synapses influences synaptic transmission and network excitability in Alzheimer's disease.

September 3, 2026The EMBO JournalOpen Access

Presynaptic accumulation of APP-CTFβ may contribute to synaptic dysfunction in Alzheimer’s disease

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To determine how the accumulation of amyloid precursor protein proteolytic fragments at excitatory synapses influences synaptic transmission and network excitability in Alzheimer's disease.
Pharmacologically modulated endogenous amyloid precursor protein (APP) processing to observe the localization and functional impact of C-terminal fragments (APP-CTFs) at excitatory synapses.
Analyzed synaptic vesicle docking, release kinetics, and network activity in cellular models alongside post-mortem brain tissue from patients with Alzheimer's disease.
Assessed the physiological effect of acute monomeric amyloid-β treatment on APP-CTFβ-mediated neuronal hyperexcitability.
Presynaptic accumulation of APP-CTFβ induced its oligomerization, enhanced synaptic vesicle docking, and caused vesicle release failure, resulting in increased neuronal network hyperexcitability.
Post-mortem Alzheimer's disease tissue confirmed elevated synaptic APP-CTFβ concentrations and enlarged excitatory presynaptic boutons.
Acute application of monomeric amyloid-β preparations reversed the neuronal network hyperexcitability triggered by presynaptic APP-CTFβ accumulation.

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Implication

Preclinical investigation uncovers presynaptic APP-CTFβ accumulation driving network hyperexcitability in Alzheimer’s disease brain tissue, suggesting an early mechanism of synaptic failure.

Cite This Study

Kapadia et al. (2026) studied this question.

synapsesocial.com/papers/6a993592636c6408cfa7ded1 https://doi.org/10.1038/s44318-026-00899-6

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Implication

Preclinical investigation uncovers presynaptic APP-CTFβ accumulation driving network hyperexcitability in Alzheimer’s disease brain tissue, suggesting an early mechanism of synaptic failure.

Presynaptic accumulation of APP-CTFβ may contribute to synaptic dysfunction in Alzheimer’s disease

Key Points

Discussion

Implication

Cite This Study

Presynaptic accumulation of APP-CTFβ may contribute to synaptic dysfunction in Alzheimer’s disease

Key Points

Discussion

Implication

Cite This Study

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