Connecting the Dots Between Hypercholesterolemia and Alzheimer’s Disease: A Potential Mechanism Based on 27-Hydroxycholesterol

Abstract

Alzheimer’s disease (AD), the most common cause of dementia, is a complex and multifactorial disease involving genetic and environmental factors, with hypercholesterolemia considered as one of the risk factors. Numerous epidemiological studies have reported a positive association between AD and serum cholesterol levels, and experimental studies also provide evidence that elevated cholesterol levels accelerate AD pathology. However, the underlying mechanism of hypercholesterolemia accelerating AD pathogenesis is not clear. Here, we review the metabolism of cholesterol in the brain and focus on the role of oxysterols, aiming to reveal the link between hypercholesterolemia and AD. 27-hydroxycholesterol (27-OHC) is the major peripheral oxysterol that flows into the brain, and it affects β-amyloid (Aβ) production and elimination as well as influencing other pathogenic mechanisms of AD. Although the potential link between hypercholesterolemia and AD is well established, cholesterol-lowering drugs show mixed results in improving cognitive function. Nevertheless, drugs that target cholesterol exocytosis and conversion show benefits in improving AD pathology. Herbs and natural compounds with cholesterol-lowering properties also have a potential role in ameliorating cognition. Collectively, hypercholesterolemia is a causative risk factor for AD, and 27-OHC is likely a potential mechanism for hypercholesterolemia to promote AD pathology. Drugs that regulate cholesterol metabolism are probably beneficial for AD, but more research is needed to unravel the mechanisms involved in 27-OHC, which may lead to new therapeutic strategies for AD.

RETRACTED ARTICLE: Polyphenols from Conyza dioscoridis (L.) ameliorate Alzheimer’s disease- like alterations through multi-targeting activities in two animal models

“…Hypercholesterolemia may play a role in the development of cognitive impairment through acceleration of the accumulation of amyloid beta peptides [80][81][82]. Park et al [83] demonstrated that hypercholesterolemia accelerated Aβ accumulation and tau pathology, which was accompanied by microglial activation and subsequent aggravation of memory impairment induced by Aβ25-35.…”

White matter injury, cholesterol dysmetabolism, and APP/Abeta dysmetabolism interact to produce Alzheimer’s disease (AD) neuropathology: A hypothesis and review

“…There is now a considerable literature on how cholesterol and ApoE interact with Abeta synthesis and transport, APP metabolism, amyloid formation and tau phosphorylation (Michikawa, 2006;Carter, 2007;Popp et al, 2013;Allinquant et al, 2014;Gamba et al, 2015;Sun et al, 2015;Fanaee-Danesh et al, 2019;Loera-Valencia et al, 2019;Chew et al, 2020;Chai et al, 2021;Nanjundaiah et al, 2021;Wu et al, 2022). In general higher plasma and brain cholesterol and its metabolites correlate with higher brain Abeta levels and lower CSF Abeta levels (Reed et al, 2014;Iriondo et al, 2020).…”

“…Increased dietary cholesterol intake promotes Abeta formation and AD pathology (Pappolla et al, 2003;Ghribi et al, 2006;Ismail et al, 2017;Liu et al, 2018;Wu et al, 2022) and tau hyperphosphorylation (Bhat and Thirumangalakudi, 2013;Park et al, 2013) and cognitive impairment (Umeda et al, 2012). Decreased cholesterol biosynthesis decreases γ-secretase activity and decreases Aβ generation (Kim et al, 2016).…”

“…Increasing blood 27-Hydroxycholesterol modulates brain cholesterol metabolism and impairs learning and memory in rats (Zhang et al, 2015) and mice (Heverin et al, 2015). Since cholesterol cannot cross the BBB while 27-hyroxycholesterol does cross, it is likely that hypercholesterolemia increase in AD risk is accounted for by influx of 27-hydroxycholesterol from blood to brain (Heverin et al, 2005(Heverin et al, , 2015Björkhem et al, 2006;Shafaati et al, 2011;Zhang et al, 2015Zhang et al, , 2018Zhang et al, , 2019Gamba et al, 2019;Wang Z. H. et al, 2021;Wang et al, 2022d;Wu et al, 2022).…”

Zeolitic-imidazolate framework (ZIF-8)-based immobilized multi-enzymes integrated with a colorimetric sensor for cholesterol assay

“…2 In addition, recent research has shown that cholesterol is essential to brain synapses and the protection of the immune system against cancer. 3,4 But aberrant levels of cholesterol in blood have been linked to numerous diseases such as hypertension, hypolipoproteinemia, 5 anemia, 6 septicemia, 7 coronary heart disease, 8 arteriosclerosis, brain thrombosis and myocardial infarction. 9 In particular, hyperlipidemia has been reported to be a major hidden danger of cardiovascular and cerebrovascular diseases.…”