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bioRxiv · 10.1101/2025.04.30.651606

Caspase cleavage of APP contributes to amyloid beta-protein induced synaptic injury

Park, G.
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Abstract

BACKGROUNDIncreasing evidence suggests that amyloid beta (A{beta}) lies at the center of Alzheimers Disease (AD) pathology and that synapses are the initial site of damage by A{beta}. Recent studies have also indicated a role for caspases in AD-related synaptic dysfunction and memory loss, but the mechanism(s) through which the caspases act remains elusive. Previous studies in cell culture indicate that cleavage of a caspase site on the intracellular domain of the amyloid precursor protein (APP) protein contributes to A{beta}-induced cell death. However, the role of this cleavage event in synaptic dysfunction has not been established. METHODSThrough a combination of intracellular and extracellular electrophysiological methods and confocal microscopy of dendritic spines, we examined the involvement of caspase-3 and amyloid-precursor protein in A{beta}-mediated synaptic dysfunction. RESULTSHere, we provide evidence that caspase activity at the intracellular domain of APP is required for acute A{beta}-induced depression of glutamatergic synapses. We find that local elevation of A{beta} levels through over-expression of the C-terminal fragment of APP (C99) failed to depress synapses if caspases were inhibited pharmacologically or in tissue lacking caspase-3. To demonstrate a link between these findings to APP, we found that A{beta} failed to depress synaptic transmission or inhibit synaptic plasticity in neurons lacking APP. To specifically test the role of caspase cleavage of the intracellular domain of APP, we introduced a mutation that inhibits caspase cleavage at site 664 to the C99 construct; this construct produced A{beta} but failed to elicit A{beta}-induced synaptic depression or spine loss, and reduced caspase-3 activity. CONCLUSIONTaken together, these results suggest an APP-dependent pathway in which caspases contribute to A{beta}-induced synaptic depression and spine loss via cleavage of APP.

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Park, G.. 2025-05-07. Caspase cleavage of APP contributes to amyloid beta-protein induced synaptic injury. https://doi.org/10.1101/2025.04.30.651606

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