Donepezil effects on cholesterol and oxysterol plasma levels of Alzheimer’s disease patients

Abstract

Cholesterol is an essential component in the structure and function of cell membranes and has been associated with the major pathological signatures of Alzheimer's disease (AD). To maintain brain cholesterol homeostasis, it is converted into 24(S)-hydroxycholesterol (24OHC) which can be driven through the blood-brain barrier. Several studies have already described a decrease in 24OHC and an increase of 27(S)-hydroxycholesterol (27OHC) in AD, as a reflection of disease burden, the loss of metabolically active neurons and the degree of structural atrophy. It is also well known that peripheral cholesterol is altered in AD patients. However, there are no data regarding effects of AD treatment in this cholesterol pathway. Since a study from our group indicated a significant increase in membrane phospholipid metabolism by donepezil, the aim of this study was to evaluate the effect of short- and long-term donepezil treatment on cholesterol and metabolites 24OHC and 27OHC in plasma of AD patients and in healthy volunteers. At baseline, we found a decrease of 24OHC (p = 0.003) in AD patients. Cholesterol levels increased with donepezil treatment (p = 0.04) but no differences were observed regarding 24OHC and 27OHC. However, these results confirm and extend previous studies demonstrating disturbed cholesterol turnover in Alzheimer's disease.

Serum 24‐hydroxycholesterol in probable Alzheimer's dementia: Reexploring the significance of a tentative Alzheimer's disease biomarker

“…This study has also claimed that the levels of 24‐hydroxycholesterol and cholesterol 24‐hydroxylase are both decreased in the post‐mortem AD brain along with downregulation of Sirtuin 1 . Thus, the clear majority of experimental data, including some elegant molecular genetic studies, tends to support the protective effect of this compound against AD pathogenesis, although a few studies have indicated the neurotoxic potential of 24‐hydroxycholesterol . In brief, the decreased 24‐hydroxycholesterol level in peripheral circulation in AD cases observed in different studies, including the present one, is very much consistent with experimental data and, further, it suggests that the deficiency of this oxysterol has a role in AD pathogenesis.…”

27‐hydroxycholesterol promotes Aβ accumulation via altering Aβ metabolism in mild cognitive impairment patients and APP/PS1 mice

“…Aβ is believed to be the essential trigger of AD pathology. Evidence has shown that 27‐OHC could increase the levels of Aβ and induce endoplasmic reticulum stress, a cellular response that is implicated in AD . It is also demonstrated in in vitro studies that Aβ could be released after 27‐OHC treatment .…”

“…Gamba et al reports that plasma levels of 27‐OHC are significantly reduced in patients with dementing disorders compared to non‐demented subjects . Moreover, it is pointed that no differences were found in the plasma levels of 27‐OHC between AD patients and the controls . The reason for this divergence might be related to the different genetic backgrounds of the population, the proportion of different stages of cognitive decline and even the distribution of age, sex and education .…”

Biomarkers for Alzheimer’s disease: from pathogenesis to drug development

“…After 6 months of treatment, there was a discrete increase in cholesterol levels, but no change in 24(S)-hydroxycholesterol levels. Although Costa et al [8] suggest a role of disturbed cholesterol turnover in AD pathogenesis, further studies using larger populations are needed.…”

“…Interestingly, there is considerable evidence suggesting a relationship between the degree of brain atrophy and plasma levels of the cholesterol metabolite 24(S)-hydroxycholesterol [7]. In this issue, Costa et al [8] found decreased plasma levels of 24(S)-hydroxycholesterol in probable AD patients (n = 30) compared with healthy controls (n = 33), whereas plasma levels of 27(S)-hydroxycholesterol and total cholesterol were not altered. Furthermore, the presence of an ApoE4 allele was not associated with cholesterol, 24(S)-hydroxycholesterol or 27(S)-hydroxycholesterol.…”