APP accumulates around dense-core amyloid plaques with presynaptic proteins in Alzheimer’s disease brain

In Alzheimer’s disease (AD), a central role is given to the extracellular deposition of Aβ peptides, remotely produced by the proteolysis of the amyloid precursor protein (APP). This contrasts with other neurodegenerative diseases which are characterized by the intraneuronal aggregation of full-length proteins such as huntingtin, α-synuclein or TDP-43. Importantly, the distribution of APP around amyloid plaques is poorly characterized. Here, we combined an extensive set of methodological and analytical tools to investigate neuropathological features of APP in the human AD hippocampus and in two mouse models of AD. We report that APP remarkably accumulates in the surrounding of dense-core amyloid plaques together with the secretases necessary to produce Aβ peptides. In addition, the Nter domain, but not the Cter domain of APP is enriched in the core of amyloid plaques uncovering a potential pathological role of the secreted APP-Nter in dense-core plaques. To investigate the subcellular compartment in which APP accumulates, we labelled neuritic and synaptic markers and report an enrichment in presynaptic proteins (Syt1, VAMP2) and phosphorylated-Tau. Ultrastructural analysis of APP accumulations reveals abundant multivesicular bodies containing presynaptic vesicles proteins and autophagosomal built-up of APP. Altogether, our data supports a role of presynaptic APP in AD pathology and highlights APP accumulations as a potential source of Aβ and Nter peptides to fuel amyloid plaques. ### Competing Interest Statement The authors have declared no competing interest.