PAT1 inversely regulates the surface Amyloid Precursor Protein level in mouse primary neurons

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.

The Rab5 activator RME-6 is required for amyloid precursor protein endocytosis depending on the YTSI motif

“…7). These results are in line with a study showing that downregulation of PAT1a, which binds the YTSI motif, leads to increased APP levels at the cell surface [54] and a more recent analysis, showing colocalization of EEA1 and PAT1a [38]. The YTSI motif of APP conforms to the tyrosine-dependent YXXФ sequence and might therefore be able to induce CME by direct binding to the μ2 subunit of AP2 [55,56].…”

APP Receptor? To Be or Not To Be

“…Increased interaction of APP with microtubule interacting proteins PAT1 and PAT1a has been reported to favor surface expression of APP in transfected cell lines, while PAT1a knockdown reduces the levels of APP at the plasma membrane [104, 105] . However, a recent study reported an inverse correlation between PAT1 expression and accumulation of endogenous cell surface APP in primary neurons, suggesting that PAT 1-APP interaction and APP trafficking might involve additional neuron-specific mechanisms [106] .…”