Atherosclerosis and Alzheimer - diseases with a common cause? Inflammation, oxysterols, vasculature

Abstract

BackgroundAging is accompanied by increasing vulnerability to pathologies such as atherosclerosis (ATH) and Alzheimer disease (AD). Are these different pathologies, or different presentations with a similar underlying pathoetiology?DiscussionBoth ATH and AD involve inflammation, macrophage infiltration, and occlusion of the vasculature. Allelic variants in common genes including APOE predispose to both diseases. In both there is strong evidence of disease association with viral and bacterial pathogens including herpes simplex and Chlamydophila. Furthermore, ablation of components of the immune system (or of bone marrow-derived macrophages alone) in animal models restricts disease development in both cases, arguing that both are accentuated by inflammatory/immune pathways. We discuss that amyloid β, a distinguishing feature of AD, also plays a key role in ATH. Several drugs, at least in mouse models, are effective in preventing the development of both ATH and AD. Given similar age-dependence, genetic underpinnings, involvement of the vasculature, association with infection, Aβ involvement, the central role of macrophages, and drug overlap, we conclude that the two conditions reflect different manifestations of a common pathoetiology.MechanismInfection and inflammation selectively induce the expression of cholesterol 25-hydroxylase (CH25H). Acutely, the production of ‘immunosterol’ 25-hydroxycholesterol (25OHC) defends against enveloped viruses. We present evidence that chronic macrophage CH25H upregulation leads to catalyzed esterification of sterols via 25OHC-driven allosteric activation of ACAT (acyl-CoA cholesterol acyltransferase/SOAT), intracellular accumulation of cholesteryl esters and lipid droplets, vascular occlusion, and overt disease.SummaryWe postulate that AD and ATH are both caused by chronic immunologic challenge that induces CH25H expression and protection against particular infectious agents, but at the expense of longer-term pathology.

Microbes and Alzheimer’s Disease

“…Polymorphisms in human CH25H govern both AD susceptibility and Aβ deposition [67], arguing that Aβ induction is likely to be among the targets of 25OHC, providing a potential mechanistic link between infection and Aβ production [68]. …”

Biotic/Abiotic Stress-Driven Alzheimer's Disease

“…Interestingly, another AMP, β-defensin 1, has similarly shown overproduction in AD patients (Williams et al, 2013). An SNP in human CH25H governs both AD susceptibility and Aβ deposition, implying Aβ induction may be a 25OHC target, and also providing a potential mechanistic link between pathogenic infection and Aβ accumulation (Papassotiropoulos et al, 2005; Lathe et al, 2014). …”

Genome-wide significant, replicated and functional risk variants for Alzheimer’s disease

“…The association between cerebrovascular atherosclerosis and AD has been examined in many cross-sectional studies (Kim et al 2016). Both Atherosclerosis and AD involve inflammation and macrophage infiltration (Lathe et al 2014). Subsequently, two canonical pathways indicative of macrophage activation [production of IL-12 and nitric oxide and reactive oxygen species (NOROS)] were among the top 5 significantly enriched pathways.…”