Abnormal brain cholesterol homeostasis in Alzheimer’s disease—a targeted metabolomic and transcriptomic study
Changes in cholesterol metabolism have been associated with an elevated risk of developing Alzheimer’s disease (AD), with several studies linking hypercholesterinemia and certain lipoprotein isoforms (ApoE4) to the disease. Pan et al. (2017) and Mahmoudian Dehkordi et al. (2019) discussed the role of bile acids in AD and cognitive decline. However, the underlying biochemical mechanism has not been fully understood.
Proposed mechanisms include the effect of “classic” cardiometabolic disease risk factors, altered lipidation of lipoproteins, and effects on lysosomal plaque clearance.
In a new study, Varma et al. add to our knowledge of how brain cholesterol metabolism affects the pathogenesis of AD. The group quantitatively analyzed free oxysterols, key intermediates of cholesterol metabolism, using post-mortem brain samples from two cohort studies (the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS)).
While free cholesterol levels were unchanged in AD patients in both cohorts, changes were spotted in selected markers for cholesterol anabolism and enzymatic and non-enzymatic cholesterol catabolism. For example, reduced lanosterol levels in the middle frontal gyrus were associated with a higher plaque burden in the presence of neurofibrillary tangles.
Lower levels of enzymatically-produced 24S-hydroxycholesterol and higher levels of 7α hydroxycholesterol were associated with selected markers of AD pathology. Higher amounts of non-enzymatically produced metabolites 5α,6α-epoxycholesterol, 5α,6β-dihydroxycholestanol, 5β,6β-epoxycholesterol, 7-ketocholesterol, and 7β-hydroxycholesterol were found in the inferior temporal gyrus in both cohorts. However, two of these metabolites (5α,6β-dihydroxycholestanol concentration and 7β-hydroxycholesterol) were reduced in AD patients in the ROS cohort only. Gene expression in cholesterol anabolism and catabolism were also altered in AD, though these changes were not observed in patients with Parkinson’s disease.
Besides decreased cholesterol biosynthesis, the findings suggest that AD pathogenesis is fueled by an increase in the conversion of cholesterol to bile acids, as well as an increase in the production of potentially toxic oxysterol metabolites. The authors discuss that the observed changes in cholesterol metabolism may have deleterious effects in two key ways: lower levels of cholesterol precursors may result in a loss of neuroprotective effects on mitochondrial energy metabolism, while lower levels of non-enzymatically produced metabolites may contribute to oxidative stress and chronic inflammation.
Finally, the study suggests that cholesterol metabolism might be a promising therapeutic target in Alzheimer’s disease.
Varma, V.R., Büsra Lüleci, H., Oommen, A.M. et al.: Abnormal brain cholesterol homeostasis in Alzheimer’s disease—a targeted metabolomic and transcriptomic study.(2021) npj aging and mechanism of disease | https://doi.org/10.1038/s41514-021-00064-9