ApoE4 upregulates the activity of mitochondria‐associated ER membranes

Abstract

In addition to the appearance of senile plaques and neurofibrillary tangles, Alzheimer's disease (AD) is characterized by aberrant lipid metabolism and early mitochondrial dysfunction. We recently showed that there was increased functionality of mitochondria‐associated endoplasmic reticulum (ER) membranes (MAM), a subdomain of the ER involved in lipid and cholesterol homeostasis, in presenilin‐deficient cells and in fibroblasts from familial and sporadic AD patients. Individuals carrying the ε4 allele of apolipoprotein E (ApoE4) are at increased risk for developing AD compared to those carrying ApoE3. While the reason for this increased risk is unknown, we hypothesized that it might be associated with elevated MAM function. Using an astrocyte‐conditioned media (ACM) model, we now show that ER–mitochondrial communication and MAM function—as measured by the synthesis of phospholipids and of cholesteryl esters, respectively—are increased significantly in cells treated with ApoE4‐containing ACM as compared to those treated with ApoE3‐containing ACM. Notably, this effect was seen with lipoprotein‐enriched preparations, but not with lipid‐free ApoE protein. These data are consistent with a role of upregulated MAM function in the pathogenesis of AD and may help explain, in part, the contribution of ApoE4 as a risk factor in the disease.

Localization and Processing of the Amyloid-β Protein Precursor in Mitochondria-Associated Membranes

“…Similar results were obtained in neuroblastoma cells expressing familial AD-linked PS2 mutations [35]. Interestingly, increased ER-mitochondria connectivity was also reported in a transgenic AD mouse model expressing mutant tau protein [65], and most recently, in cells exposed to apolipoprotein E (ApoE4), a major risk factor for developing sporadic AD [66]. These results and our data may lead to consider MAMs structural alteration as a common denominator underlying the pathogenesis of AD associated to both sporadic and APP/PS-linked familial AD mutations.…”

Mitochondria-associated ER membranes and Alzheimer disease

“…The idea that perturbed MAM behavior is a precipitating event in AD was reinforced by recent work on the differential effects of ApoE4 vs ApoE3 on MAM function [63]. Specifically, human fibroblasts and neuronal-like SH-SY5Y cells treated with astrocyte-conditioned media (ACM) from knock-in mice expressing human ApoE4 upregulated MAM function to a significantly greater extent than did ACM from ApoE3 knock-in mice [63].…”

“…Specifically, human fibroblasts and neuronal-like SH-SY5Y cells treated with astrocyte-conditioned media (ACM) from knock-in mice expressing human ApoE4 upregulated MAM function to a significantly greater extent than did ACM from ApoE3 knock-in mice [63]. Moreover, the effects of ApoE4 were apparently due to its role as a component of lipoproteins, not as the free, unlipidated protein [63], implying that its effects on MAM were related to its function in lipoprotein-mediated cholesterol trafficking and metabolism. We note that ApoE4 is recycled less efficiently than is ApoE3 [64,65], thereby causing cholesterol to accumulate in endosomes and lysosomes, which can then traffic to the ER [66].…”

Mitochondrial lipids in neurodegeneration

“…In addition, hyperactive presenilins enlarge the contact area between mitochondria and ER, thereby increasing MAM function (Area-Gomez et al 2009, 2012; Zampese et al 2011). Moreover, the AD-associated apolipoprotein E4 allele also enhances MAM activity (Tambini et al 2016). Finally, MAMs show high levels of ACAT1 as the predominant isoform of the acyl-coenzyme A cholesterol acyltransferase, an important enzyme in cholesterol metabolism (Rusinol et al 1994; Area-Gomez et al 2012) which is required for APP processing and subsequent generation of Aβ (Bryleva et al 2010; Huttunen et al 2009; Puglielli et al 2001).…”