Impact of age, hypercholesterolemia, and the vitamin D receptor on brain endogenous β‐amyloid peptide accumulation in mice

Abstract

Age, hypercholesterolemia, and vitamin D deficiency are risk factors that increase the brain accumulation of pathogenic β‐amyloid peptides (40 and 42), precursors leading to Alzheimer's disease (AD) in humans. The relative changes accompanying aging, high cholesterol, and/or treatment of calcitriol, active vitamin D receptor (VDR) ligand, under normal physiology are unknown. We examined these relative changes in C57BL/6 mice of ages 2, 4–8, and more than 10 months old, which were fed a normal or high fat / high cholesterol diet and treated with calcitriol, active ligand of the vitamin D receptor (0 or 2.5 μg/kg ×4, intraperitoneally, every other day to elicit cholesterol lowering in liver). Aβ40 but not Aβ42 accumulation in brain and lower P‐glycoprotein (P‐gp) and neprilysin protein expressions for Aβ efflux and degradation, respectively, were found to be associated with aging. But there was no trend for BACE1 (β‐secretase 1, a cholesterol‐sensitive enzyme) toward Aβ synthesis with age. In response to calcitriol treatment, P‐gp was elevated, mitigating partially the age‐related changes. Although age‐dependent decreasing trends in mRNA expression levels existed for Cyp46a1, the brain cholesterol processing enzyme, whose inhibition increases BACE1 and ApoE to facilitate microglia Aβ degradation, mRNA changes for other cholesterol transporters: Acat1 and Abca1, and brain cholesterol levels remained unchanged. There was no observable change in the mRNA expression of amyloid precursor protein (APP) and the influx (RAGE) and efflux (LRP1) transporters with respect to age, diet, or calcitriol treatment. Overall, aging poses as a risk factor contributing to Aβ accumulation in brain, and VDR‐mediated P‐gp activation partially alleviates the outcome.

Measuring Amyloid‐β Peptide Concentrations in Murine Brain with Improved ELISA Assay

“…The Aβ 40 concentrations in mouse brain in this study are similar to those found by Peng et al. (2021), and these values are higher than those for Aβ 42 . The ratio of Aβ 40 /β 42 concentration in mouse brain is about 2 for all ages.…”

“…These mice were different from those in Peng et al. (2021) (8‐week‐old, 4‐ to 8‐month‐old, and 10‐month‐old mice).…”

“…According to our modified method, the assayed brain Aβ 40 and Aβ 42 concentrations for the 8-week-old C57BL/6 mice were 7060 ± 543 (6038 to 7893) pg/g and 3520 (2005 to 4317) pg/g, respectively (Table 2). The Aβ 40 concentrations in mouse brain in this study are similar to those found by Peng et al (2021), and these values are higher than those for Aβ 42 . The ratio of Aβ 40 /β 42 concentration in mouse brain is about 2 for all ages.…”

Aging and brain free cholesterol concentration on amyloid‐β peptide accumulation in guinea pigs

“…Cholesterol is highly important in Aβ peptide processing in the brain (Di Paolo & Kim, 2011), the most cholesterol-rich organ, comprising ~20% of the entire cholesterol load (Björkhem & Meaney, 2004) that involves de novo synthesis independent of the liver (Jeske & Dietschy, 1980;Peng, Bukuroshi, et al, 2021).…”

Reply to Pluta, R. Comment on “Minich et al. Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements. Nutrients 2022, 14, 3934”

“…Separate from the established and emerging research aiming to support the shared mechanisms of vitamin D and melatonin in brain- and neurological-related disorders, there is some indication that vitamin D may play a role in amyloid [ 30 , 31 , 32 , 33 , 34 ] and tau protein [ 35 , 36 , 37 ] metabolism, which are the distinct areas that Dr. Pluta showed particular interest in, and concern about, regarding our provocative statement of query as to whether melatonin is the “next vitamin D”.…”