PDF(Pubmed)
Abstract：
We postulate that myelin injury contributes to cholesterol release from myelin and cholesterol dysmetabolism which contributes to Abeta dysmetabolism, and combined with genetic and AD risk factors, leads to increased Abeta and amyloid plaques. Increased Abeta damages myelin to form a vicious injury cycle. Thus, white matter injury, cholesterol dysmetabolism and Abeta dysmetabolism interact to produce or worsen AD neuropathology. The amyloid cascade is the leading hypothesis for the cause of Alzheimer\'s disease (AD). The failure of clinical trials based on this hypothesis has raised other possibilities. Even with a possible new success (Lecanemab), it is not clear whether this is a cause or a result of the disease. With the discovery in 1993 that the apolipoprotein E type 4 allele (APOE4) was the major risk factor for sporadic, late-onset AD (LOAD), there has been increasing interest in cholesterol in AD since APOE is a major cholesterol transporter. Recent studies show that cholesterol metabolism is intricately involved with Abeta (Aβ)/amyloid transport and metabolism, with cholesterol down-regulating the Aβ LRP1 transporter and upregulating the Aβ RAGE receptor, both of which would increase brain Aβ. Moreover, manipulating cholesterol transport and metabolism in rodent AD models can ameliorate pathology and cognitive deficits, or worsen them depending upon the manipulation. Though white matter (WM) injury has been noted in AD brain since Alzheimer\'s initial observations, recent studies have shown abnormal white matter in every AD brain. Moreover, there is age-related WM injury in normal individuals that occurs earlier and is worse with the APOE4 genotype. Moreover, WM injury precedes formation of plaques and tangles in human Familial Alzheimer\'s disease (FAD) and precedes plaque formation in rodent AD models. Restoring WM in rodent AD models improves cognition without affecting AD pathology. Thus, we postulate that the amyloid cascade, cholesterol dysmetabolism and white matter injury interact to produce and/or worsen AD pathology. We further postulate that the primary initiating event could be related to any of the three, with age a major factor for WM injury, diet and APOE4 and other genes a factor for cholesterol dysmetabolism, and FAD and other genes for Abeta dysmetabolism.
摘要：
我们假设髓鞘损伤有助于从髓磷脂和胆固醇代谢异常中释放胆固醇，这有助于Abeta代谢异常。结合遗传和AD危险因素，导致Abeta和淀粉样斑块增加。增加的Abeta损伤髓鞘形成恶性损伤循环。因此，白质损伤,胆固醇代谢异常和Abeta代谢异常相互作用以产生或恶化AD神经病理学。淀粉样蛋白级联反应是导致阿尔茨海默病(AD)的主要假设。基于这一假设的临床试验的失败提出了其他可能性。即使有可能取得新的成功（Lecanemab），目前尚不清楚这是疾病的原因还是结果。随着1993年发现载脂蛋白E4型等位基因(APOE4)是散发性的主要危险因素,晚发性AD（负荷），由于APOE是一种主要的胆固醇转运蛋白，因此人们对AD中的胆固醇越来越感兴趣。最近的研究表明,胆固醇代谢与Abeta(Aβ)/淀粉样蛋白的转运和代谢密切相关,随着胆固醇下调AβLRP1转运蛋白并上调AβRAGE受体，两者都会增加大脑Aβ。此外，在啮齿动物AD模型中操纵胆固醇转运和代谢可以改善病理和认知缺陷，或根据操纵使它们恶化。虽然白质（WM）损伤已经注意到在AD的大脑，因为阿尔茨海默氏症的初步观察，最近的研究表明，每个AD大脑的白质异常。此外，在正常个体中存在年龄相关的WM损伤,其发生较早,并且APOE4基因型更为严重。此外，在人类家族性阿尔茨海默病（FAD）中，WM损伤先于斑块和缠结形成，而在啮齿动物AD模型中，WM损伤先于斑块形成。在啮齿动物AD模型中恢复WM改善认知而不影响AD病理学。因此，我们假设淀粉样蛋白级联，胆固醇代谢异常和白质损伤相互作用以产生和/或恶化AD病理。我们进一步假设主要的启动事件可能与这三个事件中的任何一个有关，年龄是WM受伤的主要因素，饮食和APOE4和其他基因是胆固醇代谢异常的因素，和FAD和其他基因的Abeta代谢异常。
