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 identified as the biggest genetic risk factor for LOAD. However, since APOE4 is not present in all LOAD patients, genome-wide association studies of thousands of LOAD patients were undertaken to identify other genetic variants that could explain the development of LOAD. PICALM, BIN1, CD2AP, SORL1, and PLD3 are now with APOE4 among the identified genes at highest risk in LOAD that have been implicated in Aβ42 production. Recent evidence indicates that the regulation of the endocytic trafficking of the amyloid precursor protein (APP) and/or its secretases to and from sorting endosomes is determinant for Aβ42 production. Thus, here, we will review the described mechanisms, whereby these genetic risk factors can contribute to the enhanced endocytic production of Aβ42. Dissecting causal LOAD mechanisms of Aβ42 accumulation, underlying the contribution of each genetic risk factor, will be required to identify therapeutic targets for novel personalized preventive strategies.

Transmissible Endosomal Intoxication: A Balance between Exosomes and Lysosomes at the Basis of Intercellular Amyloid Propagation

“…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].…”

“…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).…”

“…Early endosomes act as a central sorting platform where cargoes can be retrieved for recycling to the PM or to the Trans-Golgi Network (TGN) whereas other cargoes remain sequestered within early endosomes that mature into MVBs [ 35 ] ( Figure 1 B). Aberrant functioning of proteins that regulate recycling or retrograde transport has been identified as a risk factor for AD [ 12 ]. In this regard, one major player implicated in the endosome-to-TGN recycling of APP and C99 is the sortilin-related receptor SORLA [ 36 ].…”

Intracellular Trafficking Mechanisms of Synaptic Dysfunction in Alzheimer’s Disease

“…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).…”

High glucose‐mediated PICALM and mTORC1 modulate processing of amyloid precursor protein via endosomal abnormalities

“…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).…”