Abstract
BackgroundThe amyloid precursor protein (APP) is a key molecule in Alzheimer disease. Its localization at the cell surface can trigger downstream signaling and APP cleavages. APP trafficking to the cell surface in neurons is not clearly understood and may be related to the interactions with its partners. In this respect, by having homologies with kinesin light chain domains and because of its capacity to bind APP, PAT1 represents a good candidate.ResultsWe observed that PAT1 binds poorly APP at the cell surface of primary cortical neurons contrary to cytoplasmic APP. Using down and up-regulation of PAT1, we observed respectively an increase and decrease of APP at the cell surface. The increase of APP at the cell surface induced by low levels of PAT1 did not trigger cell death signaling.ConclusionsThese data suggest that PAT1 slows down APP trafficking to the cell surface in primary cortical neurons. Our results contribute to the elucidation of mechanisms involved in APP trafficking in Alzheimer disease.
Highlights
The amyloid precursor protein (APP) is a key molecule in Alzheimer disease
We have previously shown that overexpression of the APP-PAT1 binding domain in the cytoplasm of primary neurons through the help of an internalization vector, leads to a very rapid increase of APP at the cell surface bound to a low amount of PAT1 triggering a cell death signal [33]
Colocalization of APP and PAT1 is poorly present at the cell surface of neurons We first observed in primary cortical neurons that paraformaldehyde (PFA) fixation at 4% caused little permeabilization at the cell surface allowing some PAT1 detection under the cell surface while additional permeabilization by 0.2% Triton X 100 allowed to detect more PAT1 in the cytoplasm (Figure 1A)
Summary
The amyloid precursor protein (APP) is a key molecule in Alzheimer disease. APP trafficking to the cell surface in neurons is not clearly understood and may be related to the interactions with its partners. Amyloid Precursor Protein (APP) is a key molecule in Alzheimer disease (AD) by the generation of its metabolites [1,2]. Able to induce neurite outgrowth in primary neurons, promote a rapid traffic of APP to the cell surface [11]. This increase of APP at the cell surface is required for reelin-induced neurite outgrowth suggesting that APP at the cell surface triggers some signaling in this model [11].
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