SNX8 Enhances Non-amyloidogenic APP Trafficking and Attenuates Aβ Accumulation and Memory Deficits in an AD Mouse

Abstract

Dysregulation of various APP trafficking components in the endosome has been previously implicated in Alzheimer’s disease (AD). Although single nucleotide polymorphisms within the gene locus encoding the endosomal component, SNX8 have been previously associated with AD, how SNX8 levels are altered and its contribution to AD onset is currently unknown. Here, we observe decreased expression of SNX8 in human AD and AD mouse brain. SNX8 predominantly localized to early and late endosomes, where SNX8 overexpression enhanced total APP levels, cell surface APP distribution and consequent soluble APPα cleavage. SNX8 depletion resulted in elevated β-amyloid (Aβ) levels, while SNX8 overexpression reduced Aβ levels in cells and in an APP/PS1 AD mouse model. Importantly, SNX8 overexpression rescued cognitive impairment in APP/PS1 mice. Together, these results implicate a neuroprotective role for SNX8 in enhancing non-amyloidogenic APP trafficking and processing pathways. Given that endosomal dysfunction is an early event in AD, restoration of dysfunctional endosomal components such as SNX8 may be beneficial in future therapeutic strategies.

A PX-BAR protein Mvp1/SNX8 and a dynamin-like GTPase Vps1 drive endosomal recycling

“…SNX8 forms a homodimer and exhibits membrane deformation activity in vitro (Weering et al, 2012). Although SNX8 has been linked to several diseases, especially AD (Rosenthal et al, 2012; Xie et al, 2019), its molecular function has not been analyzed in detail. When GFP-SNX8 was expressed in Hela cells, it showed punctate structures that colocalized with the early endosome protein EEA1, as reported previously (Figure 7B-(i); Dyve et al, 2009).…”

“…Interestingly, two single nucleotide polymorphisms within the SNX8 gene locus are associated with late-onset Alzheimer’s disease (AD) (Rosenthal et al, 2012). Xie et al report that the SNX8 expression level is significantly lower in AD patients and APP/PS1 AD mouse brain (Xie et al, 2019). Overexpression of SNX8 suppresses the accumulation of fragments of amyloid precursor protein (Aβ).…”

Sorting Out Sorting Nexins Functions in the Nervous System in Health and Disease

“…Thus, authors hypothesize that SNX4 links membrane carrier formation to motor driven movement. SNX7 and SNX8 have been recently associated with infection and with brain pathology [50][51][52][53]. Their function remains yet to be mechanistically elucidated, particularly concerning BAR domains' contribution.…”

“…SNX8H. sapiens form is highly expressed in the spleen; Has a C-terminal BAR domain, involved in membrane tubulation [50,53,118,119]. SNX9 H. sapiens form is ubiquitously expressed; In addition to the BAR domain, it also displays a N-terminal SH3 protein-interacting motif, reported to bind to polyproline and hydrophobic aminoacidic sequences [14,[120][121][122][123].…”

Enhancing α-secretase Processing for Alzheimer’s Disease—A View on SFRP1

“…A primary determinant of whether APP is first subjected to αor β-cleavage is dependent on its co-trafficking and membrane residence with BACE1 and ADAM10. In this regard, modulators of exocytic and endocytic membrane traffic such as members of the sorting nexin family SNX27 [47] and SNX8 [48], the polarity protein Par3 [49], the microtubule binding protein superior cervical ganglion 10 (SCG10) and endocytic itinerary regulators such as huntingtin-associated protein 1 (HAP1), have all been shown to promote non-amyloidogenic APP processing. The trafficking and stabilization of ADAM10 and its substrates APP and Notch at the plasma membrane and endosomes are also regulated by members of the tetraspanin family [50][51][52].…”