P003 - APP ACCUMULATIONS AROUND DENSE-CORE AMYLOID PLAQUES AS A NOVEL HALLMARK OF ALZHEIMER’S DISEASE
Abstract
Aims
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. Here, we aimed at investigating whether full-length APP accumulates intracellularly in AD.
Methods
We performed immunofluorescent co-labelings in human hippocampal sections followed by quantitative analyses of hallmarks density, intensity and colocalization.
Results
We report that in the human AD hippocampus, APP remarkably accumulates in the surrounding of dense-core amyloid plaques. These APP accumulations contain APP secretases necessary to produce Aβ peptides and are enriched in presynaptic proteins (Syt1, VAMP2). 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. Ultrastructural analysis of APP accumulations reveals abundant multivesicular bodies containing presynaptic vesicles proteins and autophagosomal built-up of APP.
Conclusions
Altogether, our data reveals a key role of intraneuronal full-length APP in AD mechanism and highlights APP accumulations as potential sources of Aβ and Nter peptides to fuel amyloid plaques.
