2018
DOI: 10.1007/s00018-018-2825-9
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Impact of late-onset Alzheimer’s genetic risk factors on beta-amyloid endocytic production

Abstract: The increased production of the 42 aminoacids long beta-amyloid (Aβ42) peptide has been established as a causal mechanism of the familial early onset Alzheimer's disease (AD). In contrast, the causal mechanisms of the late-onset AD (LOAD), that affects most AD patients, remain to be established. Indeed, Aβ42 accumulation has been detected more than 30 years before diagnosis. Thus, the mechanisms that control Aβ accumulation in LOAD likely go awry long before pathogenesis becomes detectable. Early on, APOE4 was… Show more

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Cited by 38 publications
(25 citation statements)
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“…In this regard, one major player implicated in the endosome-to-TGN recycling of APP and C99 is the sortilin-related receptor SORLA [36]. SORLA is highly expressed in the brain and several genetic variants are associated with a higher risk of developing SAD [12,13]. Furthermore, a decreased expression of genes that encode retromer components (e.g., vacuolar protein sorting Vps 35 and Vps26 responsible for retrograde transport of APP, C99, and BACE1) and Rab11A (involved in endosomal recycling), was also observed in AD patients [37].…”
Section: From Early Endosome To Mvb: a Sorting Station For App And Itmentioning
confidence: 99%
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“…In this regard, one major player implicated in the endosome-to-TGN recycling of APP and C99 is the sortilin-related receptor SORLA [36]. SORLA is highly expressed in the brain and several genetic variants are associated with a higher risk of developing SAD [12,13]. Furthermore, a decreased expression of genes that encode retromer components (e.g., vacuolar protein sorting Vps 35 and Vps26 responsible for retrograde transport of APP, C99, and BACE1) and Rab11A (involved in endosomal recycling), was also observed in AD patients [37].…”
Section: From Early Endosome To Mvb: a Sorting Station For App And Itmentioning
confidence: 99%
“…C99 and subsequent Aβ can also be potentially generated from the intermediate APP product CTFη (produced after cleavage of APP by the recently described η-secretase [ 10 , 11 ]). Genome wide association (GWAS)-based analyses have identified several genetic factors for LOAD (e.g., APOE4, BIN-1, PICALM, CD2AP or PLD3) to be involved in endosomal APP trafficking [ 12 , 13 ]. A large body of evidence demonstrates that the trafficking of APP and its proteases forms a major regulatory process of APP cleavage and that endosomes are a major site of the amyloidogenic APP cleavage [ 14 ] ( Figure 1 B).…”
Section: From Early Endosome To Mvb: a Sorting Station For App Andmentioning
confidence: 99%
See 1 more Smart Citation
“…Indeed, it is essential to keep in mind that these biological pathways intersect; for example, lipid metabolism influences trafficking at many levels (Huijbregts et al, 2000) and trafficking in microglia influences the immune response (McQuade and Blurton-Jones, 2019). Most attention has been given to how the loss of function of these genes impacts Aβ, generation (reviewed in Guimas Almeida et al, 2018), aggregation (Zhang et al, 2018), and clearance (Van Acker et al, 2019). Recently reviewed data indicates that LOAD microglia risk genes may impact synapses (Rajendran and Paolicelli, 2018).…”
Section: Introductionmentioning
confidence: 99%
“…Abnormalities in the early endosome can be the result of numerous factors, including the up‐regulation of endocytic genes, increased endocytosis, and the overactivation of Rab5, which is a small GTPase that is a marker of the early endosome (Nixon, 2017). According to a genome‐wide association study, endocytic genes are risk factors for AD via mechanisms related to the impairment of trafficking (Guimas Almeida, Sadat Mirfakhar, Perdigao, & Burrinha, 2018). The allelic variants of those factors aggravate the effects of DM on cognitive decline (McFall, Wiebe, Vergote, Anstey, & Dixon, 2015).…”
Section: Introductionmentioning
confidence: 99%