APP accumulates with presynaptic proteins around amyloid plaques: A role for presynaptic mechanisms in Alzheimer's disease?

In Alzheimer's disease (AD), the distribution of the amyloid precursor protein (APP) and its fragments other than amyloid beta, has not been fully characterized. Here, we investigate the distribution of APP and its fragments in human AD brain samples and in mouse models of AD in reference to its proteases, synaptic proteins, and histopathological features characteristic of the AD brain, by combining an extensive set of histological and analytical tools. We report that the prominent somatic distribution of APP observed in control patients remarkably vanishes in human AD patients to the benefit of dense accumulations of extra‐somatic APP, which surround dense‐core amyloid plaques enriched in APP‐Nter. These features are accentuated in patients with familial forms of the disease. Importantly, APP accumulations are enriched in phosphorylated tau and presynaptic proteins whereas they are depleted of post‐synaptic proteins suggesting that the extra‐somatic accumulations of APP are of presynaptic origin. Ultrastructural analyses unveil that APP concentrates in autophagosomes and in multivesicular bodies together with presynaptic vesicle proteins. Altogether, alteration of APP distribution and its accumulation together with presynaptic proteins around dense‐core amyloid plaques is a key histopathological feature in AD, lending support to the notion that presynaptic failure is a strong physiopathological component of AD.