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Blocking cholesterol storage to treat Alzheimer's disease

Chang, Ta Yuan, Chang, Catherine C. Y., Harned, Taylor C., De La Torre, Adrianna L., Lee, Junghoon, Huynh, Thao N., Gow, James G.·2021·Exploration of Neuroprotective Therapy
DOI 10.37349/ent.2021.00014PMC PMC8863366
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Abstract

Cholesterol serves as an essential lipid molecule in various membrane organelles of mammalian cells. The metabolites of cholesterol also play important functions. Acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1), also named as sterol O-acyltransferase 1, is a membrane-bound enzyme residing at the endoplasmic reticulum (ER). It converts cholesterol to cholesteryl esters (CEs) for storage, and is expressed in all cells. CEs cannot partition in membranes; they can only coalesce as cytosolic lipid droplets. Excess CEs are found in the vulnerable region of the brains of patients with late-onset Alzheimer’s disease (AD), and in cell and mouse models for AD. Reducing CE contents by genetic inactivation of ACAT1, or by pharmacological inhibition of ACAT is shown to reduce amyloidopathy and other hallmarks for AD. To account for the various beneficial actions of the ACAT1 blockade (A1B), a working hypothesis is proposed here: the increase in CE contents observed in the AD brain is caused by damages of cholesterol-rich lipid rafts that are known to occur in neurons affected by AD. These damages cause cholesterol to release from lipid rafts and move to the ER where it will be converted to CEs by ACAT1. In addition, the increase in CE contents may also be caused by overloading with cholesterol-rich substances, or through activation of ACAT1 gene expression by various pro-inflammatory agents. Both scenarios may occur in microglia of the chronically inflamed brain. A1B ameliorates AD by diverting the cholesterol pool destined for CE biosynthesis such that it can be utilized more efficiently to repair membrane damage in various organelles, and to exert regulatory actions more effectively to defend against AD. To test the validity of the A1B hypothesis in cell culture and in vivo, the current status of various anti-ACAT1 agents that could be further developed is briefly discussed.

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Crossref · 10.37349/ent.2021.00014

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  • ACAT1 inhibitors reduce Aβ-induced neurotoxicity.

    “ACAT1 inhibitors reduce Aβ‐induced neurotoxicity (reviewed in Shibuya et al. 10 and Chang et al. 11 ).”

    From Inhibition of Acyl‐CoenzymeA: Cholesterol Acyltransferase 1 promotes shedding of soluble triggering receptor on myeloid cells 2 (TREM2) and low‐density lipoprotein receptor 1 (LRP1)‐dependent phagocytosis of amyloid beta protein in microglia (2025) · cites this paper as [11]

    The ‘ACAT1 blockade and AD’ section reports that ACAT1 blockade increases clearance of Aβ oligomers in preclinical models. The ‘Cholesterol loading, CE content, and the A1B hypothesis’ section proposes that blockade helps repair membranes damaged by oligomeric Aβ. These passages support a protective rationale, but they do not report a direct reduction in Aβ-induced neurotoxicity by ACAT1 inhibitors. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Previous studies using commercial ACAT inhibitors including AVAS, and ACAT-knockout mice, show reduced AD-like pathology and APP processing in familial AD-transgenic mice.

    “Previous studies using commercial ACAT inhibitors, including avasimibe (AVAS), as well as ACAT-knock out (KO) mice, exhibit reduced AD-like pathology and amyloid precursor protein (APP) processing in familial AD (FAD)-transgenic (Tg) mice.”

    From Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation (2023) · cites this paper as [69]

    The “ACAT1 blockade and AD” section reports that ACAT1 gene ablation ameliorates amyloid pathology in AD mice and that blockade lowers mutant hAPP protein in an AD mouse model. The “Small molecule ACAT inhibitors to treat atherosclerosis or AD” section reports reduced amyloid pathology with CP113818, not avasimibe. Our copy does not establish reduced APP processing or an avasimibe effect in familial AD-transgenic mice; page numbers are unavailable in the indexed copy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Cholesterol mobilization by ACAT inhibition in microglia can promote autophagy and lysosomal biogenesis, leading to increased clearance of oAβ.

    “cholesterol mobilization by ACAT inhibition in microglia can promote autophagy and lysosomal biogenesis, leading to an increased clearance of oAβ [69–71, 77].”

    From Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation (2023) · cites this paper as [69]

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Metadata

Authors
Chang, T. Y., Chang, C. C. Y., Harned, T. C., De La Torre, A. L., Lee, J., Huynh, T. N., & Gow, J. G.
Affiliations
Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
ORCID
Venue
Exploration of Neuroprotective Therapy
Publisher
Open Exploration Publishing
Published
2021-12-30
Volume
1
Issue
3
Pages
173-184
DOI
10.37349/ent.2021.00014
PMC
PMC8863366
Cited by
28
References
16
Language
en
Licence
doi.org/10.37349/Open_Exploration_Crossmark_Policy (unspecified)
Funders
National Institutes of Health (AG AG037609)

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