CYP46A1 inhibition, brain cholesterol accumulation and neurodegeneration pave the way for Alzheimer’s disease

Abstract

Abnormalities in neuronal cholesterol homeostasis have been suspected or observed in several neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and Huntington's disease. However, it has not been demonstrated whether an increased abundance of cholesterol in neurons in vivo contributes to neurodegeneration. To address this issue, we used RNA interference methodology to inhibit the expression of cholesterol 24-hydroxylase, encoded by the Cyp46a1 gene, in the hippocampus of normal mice. Cholesterol 24-hydroxylase controls cholesterol efflux from the brain and thereby plays a major role in regulating brain cholesterol homeostasis. We used an adeno-associated virus vector encoding short hairpin RNA directed against the mouse Cyp46a1 mRNA to decrease the expression of the Cyp46a1 gene in hippocampal neurons of normal mice. This increased the cholesterol concentration in neurons, followed by cognitive deficits and hippocampal atrophy due to apoptotic neuronal death. Prior to neuronal death, the recruitment of the amyloid protein precursor to lipid rafts was enhanced leading to the production of β-C-terminal fragment and amyloid-β peptides. Abnormal phosphorylation of tau and endoplasmic reticulum stress were also observed. In the APP23 mouse model of Alzheimer's disease, the abundance of amyloid-β peptides increased following inhibition of Cyp46a1 expression, and neuronal death was more widespread than in normal mice. Altogether, these results suggest that increased amounts of neuronal cholesterol within the brain may contribute to inducing and/or aggravating Alzheimer's disease.

Expression levels of 39 Cyp mRNAs in the mouse brain and neuroblastoma cell lines, C-1300N18 and NB2a – strong expression of Cyp1b1

“…Therefore, it is crucial for the disproportionally high level of cholesterol in the mammalian brain to be strictly controlled by the enzyme activity of CYP46A1. A previous study on siR-NA suggested that CYP46A1 plays an important role in the induction and/or aggravation of Alzheimer's disease through the degeneration of neural cholesterol homeostasis (Djelti et al, 2015).…”

Mapping of the Allosteric Site in Cholesterol Hydroxylase CYP46A1 for Efavirenz, a Drug That Stimulates Enzyme Activity

“…Cyp46a1 Ϫ/Ϫ mice have severe deficiencies in spatial, associative, and motor learning and in hippocampal long-term potentiation (5). Normal mice with suppressed hippocampal CYP46A1 expression have increased neuronal cholesterol in the hippocampus, cognitive deficits, hippocampal atrophy, aberrant electrical activities, and, ultimately, neuronal death (19,20). Thus, CYP46A1 activity is important for normal brain function.…”

Tau Spread, Apolipoprotein E, Inflammation, and More

“…Consistent with this long-held hypothesis, experiments by Djelti and colleagues observed significantly elevated free cholesterol when the mRNA of the metabolic enzyme CYp46a1 , which regulates neuronal cholesterol content, was inhibited 46 . When investigators isolated lipid rafts from mouse hippocampi on sucrose gradients, APP and Aβ peptide levels were increased and tau phosphorylation was observed.…”