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Caspase Activation and Caspase-Mediated Cleavage of APP Is Associated with Amyloid β-Protein-Induced Synapse Loss in Alzheimer's Disease.

Abstract：

:Amyloid β-protein (Aβ) toxicity is hypothesized to play a seminal role in Alzheimer's disease (AD) pathogenesis. However, it remains unclear how Aβ causes synaptic dysfunction and synapse loss. We hypothesize that one mechanism of Aβ-induced synaptic injury is related to the cleavage of amyloid β precursor protein (APP) at position D664 by caspases that release the putatively cytotoxic C31 peptide. In organotypic slice cultures derived from mice with a knock-in mutation in the APP gene (APP D664A) to inhibit caspase cleavage, Aβ-induced synaptic injury is markedly reduced in two models of Aβ toxicity. Loss of dendritic spines is also attenuated in mice treated with caspase inhibitors. Importantly, the time-dependent dendritic spine loss is correlated with localized activation of caspase-3 but is absent in APP D664A cultures. We propose that the APP cytosolic domain plays an essential role in Aβ-induced synaptic damage in the injury pathway mediated by localized caspase activation.

journal_name

Cell Rep

journal_title

Cell reports

authors

Park G,Nhan HS,Tyan SH,Kawakatsu Y,Zhang C,Navarro M,Koo EH

doi

10.1016/j.celrep.2020.107839

subject

Has Abstract

pub_date

2020-06-30 00:00:00

pages

107839

issue

13

issn

2211-1247

pii

S2211-1247(20)30820-2

journal_volume

31

pub_type

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