Abstract
The amyloid hypothesis posits that the production of β-amyloid (Aβ) aggregates leads to neurodegeneration and cognitive decline associated with AD. Aβ is produced by sequential cleavage of the amyloid precursor protein (APP) by β- and γ-secretase. While nascent APP is well known to transit to the endosomal/ lysosomal system via the cell surface, we have recently shown that APP can also traffic to lysosomes intracellularly via its interaction with AP-3. Because AP-3 interacts with cargo protein via interaction with tyrosine motifs, we mutated the three tyrosines motif in the cytoplasmic tail of APP. Here, we show that the YTSI motif interacts with AP-3, and phosphorylation of the serine in this motif disrupts the interaction and decreases APP trafficking to lysosomes. Furthermore, we show that phosphorylation at this motif can decrease the production of neurotoxic Aβ 42. This demonstrates that reducing APP trafficking to lysosomes may be a strategy to reduce Aβ 42 in Alzheimer’s disease.
Highlights
Alzheimer’s disease (AD) is characterized by the accumulation of extracellular plaques in the brains of AD patients composed of β-amyloid (Aβ) peptides
The Y709A decreased intracellular trafficking to the lysosome while the Y743A mutations significantly decreased the fraction of amyloid precursor protein (APP) delivered to lysosomes from the cell surface and by intracellular trafficking (Figs 1–3)
The C-terminal of APP has been shown to bind to a number of adaptor proteins, which act to regulate the function of APP
Summary
Alzheimer’s disease (AD) is characterized by the accumulation of extracellular plaques in the brains of AD patients composed of β-amyloid (Aβ) peptides. Aβ is derived from the amyloid precursor protein (APP), a type 1 transmembrane glycoprotein. To produce Aβ, APP is cleaved first by the β-secretase, which releases the soluble APPβ ectodomain, leaving a 99-residue βcarboxyl terminal fragment (βCTF). The βCTF is cleaved by γ-secretase to produce Aβ species varying from 38–43 residues and an APP intracellular domain. The subcellular localization of these cleavage events is unclear. For example the Golgi apparatus, plasma membrane, and autophagosomes [1,2,3,4] have been implicated in Aβ production. Many studies show that nascent APP is cleaved after endocytosis from the cell surface into
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