https://www.frontiersin.org/articles/10 ... 90372/full
Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects
Aging Neurosci., 24 June 2021
Femke M. Feringa and Rik van der Kant
DOI: 10.3389/fnagi.2021.690372
This article seems quite comprehensive. It includes a section discussing ApoE variant interactions with brain lipid metabolism.While the central nervous system compromises 2% of our body weight, it harbors up to 25% of the body’s cholesterol. Cholesterol levels in the brain are tightly regulated for physiological brain function, but mounting evidence indicates that excessive cholesterol accumulates in Alzheimer’s disease (AD), where it may drive AD-associated pathological changes. This seems especially relevant for late-onset AD, as several of the major genetic risk factors are functionally associated with cholesterol metabolism.
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In this review, we will discuss the basic regulation of cholesterol homeostasis at the cellular level, and how crosstalk between different brain-cell types regulates “healthy” cholesterol homeostasis in the human brain. We will then discuss how brain cholesterol metabolism is affected by aging and how neuronal cholesterol can contribute to downstream AD pathologies such as Amyloid- and Tau accumulation. Next, we will examine the contribution of human-specific AD risk polymorphisms to cholesterol dyshomeostasis and gliosis in different brain cell types, an area of research that greatly benefits from the development of CRISPR gene-editing and iPSC techniques. Lastly, we will formulate some of the major questions still outstanding in the field, and how they could be addressed to develop disease-modifying interventions for AD based on our knowledge of cholesterol metabolism in AD.
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A better mechanistic understanding of the cholesterol-dependent pathways that drive (early) AD development will also uncover novel (cell type) specific targets for rational drug discovery. An example of such a drug discovery effort for brain-lipid targeting drugs is the discovery that Efavirenz, an FDA approved HIV-drug, activates the neuronal specific enzyme CYP46A1 to promote conversion of excess cholesterol to 24S-OHC that can be secreted from the brain via the BBB. Efavirenz lowered pTau levels in iPSC-derived neurons from AD patients and improved behavior in 5xFAD mice (Petrov and Pikuleva, 2019; Petrov et al., 2019; van der Kant et al., 2019). A phase I clinical trial with intermediate-to-high doses of Efavirenz has started in patients with MCI in the United States (Nugent et al., 2020) and a similar trial with low-dose Efavirenz is planned to start in the Netherlands.