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

Abstract

Amyloid ?-protein (A?) toxicity is hypothesized to play a seminal role in Alzheimer's disease (AD) pathogenesis. However, it remains unclear how A? causes synaptic dysfunction and synapse loss. We hypothesize that one mechanism of A?-induced synaptic injury is related to the cleavage of amyloid ? 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, A?-induced synaptic injury is markedly reduced in two models of A? 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 A?-induced synaptic damage in the injury pathway mediated by localized caspase activation. � 2020 The AuthorsPark et al. show that inhibition of amyloid precursor protein (APP) C terminus cleavage by D664A mutation prevents A?-induced local caspase activation, leading to localized synaptic injury. � 2020 The Authors