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

Aging 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? DISCUSSION:
Both 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
beta, 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, Abeta involvement, the central role of macrophages, and drug
overlap, we conclude that the two conditions reflect different
manifestations of a common pathoetiology.Mechanism: Infection 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.

SUMMARY: We 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


Convergence of genes implicated in Alzheimer's disease on the cerebral cholesterol shuttle: APP, cholesterol, lipoproteins, and atherosclerosis

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