ACAT1/SOAT1 As a Therapeutic Target for Alzheimer’s Disease

Blocking ACAT1, the main cellular cholesterol storage enzyme, may be a promising approach for treating Alzheimer's disease

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease that causes difficulty in cognitive functions, including memory, speech and perception, etc. AD is the most common cause of dementia in developed countries. Currently available treatments for AD improve symptoms but they do not provide a cure.

The pathological hallmarks of AD in the brain consist of extracellular amyloid plaques, mainly composed of amyloid-β (Aβ) peptides and intracellular neurofibrillary tangles, mainly consisting of hyperphosphorylated forms of tau. Aβ and tau can interact with each other synergistically to trigger neurotoxicity. Thus, reducing brain levels of Aβ and/or misfolded/aggregated tau and/or hyperphosphorylated tau are attractive strategies to treat AD.

Cholesterol metabolism is closely associated with AD at several stages. The enzyme acyl-CoA:cholesterol acyltransferase 1(ACAT1), also known as sterol O-acyltransferase 1; SOAT1, plays important roles in cellular cholesterol homeostasis. ACAT1 converts free cholesterol to cholesteryl esters to prevent overaccumulation of free cholesterol at cellular membranes. Recent studies have shown that blocking ACAT1 in mouse models and in cell culture produces several beneficial effects on AD. First, blocking ACAT1 diminishes Aβ production by reducing full-length human amyloid precursor protein (APP). Second, ACAT1 blockage promotes autophagy-mediated lysosome biogenesis to enhance clearance of Aβ in microglia.Third, blocking ACAT1 upregulates autophagy in neurons and promote degradation of tau before it becomes hyperphosphorylated. These studies suggest that ACAT1 can be a novel therapeutic target to treat AD.

We have recently reviewed the experimental evidence supporting the notion that ACAT1 blockage is a promising approach for treating AD (1). In the review, We have described various mechanisms that may account for the beneficial effects of ACAT1 blockage on AD. We have also discussed the potential usage of currently available ACAT inhibitors to treat AD.

1. Y Shibuya, CCY Chang, TY Chang. ACAT1/SOAT1 as a therapeutic target for Alzheimer's disease Future Medicinal Chemistry 2015; 7(18): 2451-2467.

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Ta Yuan Chang

Professor, The Geisel School of Medicine at Dartmouth

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