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

Abstract

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.

The amyloid precursor protein regulates synaptic transmission at medial perforant path synapses

“…In line with these findings, we here provide evidence that presynaptic APP -which might promote localized actions of Aβ at presynaptic sites -is essential to restrain excitatory synaptic transmission at medial perforant path synapses on dentate granule cells. These findings support recent evidence on the role of presynapses in the pathogenesis of Alzheimer's disease (Barthet and Mulle, 2020;Jorda-Siquier et al, 2022). In support of a restraining effect of APP and its proteolytic cleavage products, we here show at the level of connected pairs of neurons that presynaptic APP controls the efficacy and strength of perforant path synapses.…”

Familial Alzheimer’s disease mutation undermines axonal transport by enhancing dynactin recruitment to the APP motor assemblies

“…Our findings fuel the hypothesis that impairments in axonal transport underlie the axonal pathology and pathogenesis of AD 1,2,37,38 . Genetic manipulation of APP 24 , its proteolytic machinery 22,25,39 and of all other major proteins linked to AD including tau 40,41 and ApoE 42 in flies and mice produces invariably axonal pathology reminiscent of the one described in molecular motor deficiencies 43 .…”

Novel small molecular compound 2JY-OBZ4 alleviates AD pathology in cell models via regulating multiple targets

“…Extracellular amyloid plaque is a pathological hallmark of AD, with Aβ as its major component [ 3 , 35 ]. Compared to Aβ40, Aβ42 is more prone to aggregation, owning to its increased hydrophobicity of expanded C terminus [ 36 , 37 ].…”

“…BACE1 inhibitor could reduce Aβ generation in AD mice brains and AD patients’ brains [ 41 ]. In particular, both BACE1 and PSEN1 are found within amyloid plaque of human AD brain [ 35 ]. In our research, increased PSEN1 and decreased BACE1 were observed in N2a-hAPP cells treated with 2JY-OBZ4.…”