Cholesterol and its oxidative derivative
27-hydroxycholesterol (27-OHC), synthesized by CYP27A1, play an important role in
Alzheimer's disease (AD) and phosphorylation of tau might be partly responsible for its pathogenesis. To investigate whether
cholesterol and 27-OHC affected learning and memory through autophagy-mediated phosphorylation of tau, male C57BL/6J mice were administrated with 2%
cholesterol diet, CYP27A1-short-hairpin
RNA (CYP27A1-shRNA) and
3-methyladenine (3-MA). The results show that
dietary cholesterol induces learning and memory impairment by upregulating the expression of brain CYP27A1 and increasing the levels of 27-OHC and
24S-hydroxycholesterol (24S-OHC). The expressions of total-tau (t-tau), phosphorylated-tau (p-
tau) protein,
glycogen synthase kinase-3β (GSK-3β) and
cyclin-dependent kinase 5 (CDK5) are also significantly upregulated in this group. In addition, reduced expressions of
Beclin-1 protein and
microtubule-associated protein 1 light chain 3 (LC3B)
mRNA, over-expression of
mammalian target of rapamycin (
mTOR) protein suggest that autophagy is impaired during
cholesterol burden. However, using of CYP27A1-shRNA remarkably downregulates the expression of brain CYP27A1. Decreased 27-OHC levels in serum and brain, lower expressions of t-tau and p-
tau protein are observed in mice treated with CYP27A1-shRNA+2%
cholesterol diet. Furthermore, 3-MA causes lower
Beclin-1, higher mTOR and p62 on both gene and
protein levels, while the expression of t-tau, p-tau, GSK-3β and CDK5 are upregulated, demonstrating that impaired autophagy disturbs the clearance of tau. These findings suggest that
dietary cholesterol induces the accumulation and phosphorylation of tau and the mechanism might be associated with impaired autophagy. And our results indicate 27-OHC might be an importance bridge between
cholesterol and
cognitive decline.