Relationships of brain cholesterol and cholesterol biosynthetic enzymes to Alzheimer’s pathology and dementia in the CFAS population-derived neuropathology cohort

IF 2.4 4区 医学 Q3 NEUROSCIENCES
Hemant Mistry , Connor D. Richardson , Adrian Higginbottom , Bridget Ashford , Saif U. Ahamed , Zoe Moore , Fiona E. Matthews , Carol Brayne , Julie E. Simpson , Stephen B. Wharton , on behalf of the Cognitive Function and Ageing Study
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Abstract

Altered cholesterol metabolism is implicated in brain ageing and Alzheimer’s disease. We examined whether key genes regulating cholesterol metabolism and levels of brain cholesterol are altered in dementia and Alzheimer’s disease neuropathological change (ADNC). Temporal cortex (n = 99) was obtained from the Cognitive Function and Ageing Study. Expression of the cholesterol biosynthesis rate-limiting enzyme HMG-CoA reductase (HMGCR) and its regulator, SREBP2, were detected using immunohistochemistry. Expression of HMGCR, SREBP2, CYP46A1 and ABCA1 were quantified by qPCR in samples enriched for astrocyte and neuronal RNA following laser-capture microdissection. Total cortical cholesterol was measured using the Amplex Red assay. HMGCR and SREBP2 proteins were predominantly expressed in pyramidal neurones, and in glia. Neuronal HMGCR did not vary with ADNC, oxidative stress, neuroinflammation or dementia status. Expression of HMGCR neuronal mRNA decreased with ADNC (p = 0.022) and increased with neuronal DNA damage (p = 0.049), whilst SREBP2 increased with ADNC (p = 0.005). High or moderate tertiles for cholesterol levels were associated with increased dementia risk (OR 1.44, 1.58). APOE ε4 allele was not associated with cortical cholesterol levels. ADNC is associated with gene expression changes that may impair cholesterol biosynthesis in neurones but not astrocytes, whilst levels of cortical cholesterol show a weak relationship to dementia status.

CFAS 群体衍生神经病理学队列中大脑胆固醇和胆固醇生物合成酶与阿尔茨海默氏症病理和痴呆症的关系
胆固醇代谢改变与大脑老化和阿尔茨海默病有关。我们研究了调节胆固醇代谢的关键基因和脑胆固醇水平在痴呆症和阿尔茨海默病神经病理改变(ADNC)中是否发生改变。颞叶皮层(n=99)取自认知功能与老化研究(Cognitive Function and Ageing Study)。采用免疫组化方法检测胆固醇生物合成限速酶 HMG-CoA 还原酶(HMGCR)及其调节因子 SREBP2 的表达。在激光捕获显微切割后富集了星形胶质细胞和神经元 RNA 的样本中,通过 qPCR 对 HMGCR、SREBP2、CYP46A1 和 ABCA1 的表达进行量化。皮质总胆固醇采用 Amplex Red 检测法进行测定。HMGCR和SREBP2蛋白主要在锥体神经元和胶质细胞中表达。神经元 HMGCR 不随 ADNC、氧化应激、神经炎症或痴呆状态而变化。HMGCR神经元mRNA的表达随ADNC的增加而减少(p=0.022),随神经元DNA损伤的增加而增加(p=0.049),而SREBP2则随ADNC的增加而增加(p=0.005)。胆固醇水平的高分位或中分位与痴呆风险增加有关(OR 1.44,1.58)。APOE ε4等位基因与皮质胆固醇水平无关。ADNC与基因表达变化有关,这些变化可能会损害神经元的胆固醇生物合成,但不会损害星形胶质细胞,而皮质胆固醇水平与痴呆状态关系不大。
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来源期刊
Neuroscience Research
Neuroscience Research 医学-神经科学
CiteScore
5.60
自引率
3.40%
发文量
136
审稿时长
28 days
期刊介绍: The international journal publishing original full-length research articles, short communications, technical notes, and reviews on all aspects of neuroscience Neuroscience Research is an international journal for high quality articles in all branches of neuroscience, from the molecular to the behavioral levels. The journal is published in collaboration with the Japan Neuroscience Society and is open to all contributors in the world.
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