Alzheimer's disease as homeostatic responses to age-related myelin breakdown.
Alzheimer's disease as homeostatic responses to age-related myelin breakdown.
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DOI：
10.1016/j.neurobiolaging.2009.08.007
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发表时间：
2011-08
影响因子：
4.2
通讯作者：
Bartzokis G
中科院分区：
文献类型：
--
作者：
Bartzokis G
阿尔茨海默病（AD）的淀粉样蛋白假说（AH）认为阿尔茨海默病的根本原因是大脑中β淀粉样蛋白（Aβ）的积累。淀粉样蛋白前体蛋白（APP）和早老素的遗传缺陷增加了Aβ的产生并导致家族性AD (FAD)，这一观察结果支持了这一假设。AH被广泛接受，但不能解释一些重要现象，包括最近的临床试验失败，即使成功地减少了Aβ沉积，也不能影响人类痴呆症。本文从人类大脑髓磷脂模型的更广泛的总体视角来看待AH，该模型侧重于功能性脑回路，除了神经元和突触外，还包括白质和髓磷脂。该模型提出，人类大脑最近进化和广泛的髓鞘形成是我们独特能力和对高度流行的年龄相关神经精神疾病（如晚发型AD (LOAD)）易感性的基础。它认为少突胶质细胞及其产生的髓磷脂对神经回路功能至关重要，而且特别容易受到损伤。这一观点重新定义了关键的观察结果，如轴突运输中断，轴突肿胀/样体和神经斑块的形成，以及作为稳态髓磷脂修复过程副产物的蛋白沉积，如Aβ和tau。它描述了经验可测试的FAD和LOAD基因的作用机制，并提供了“上游”治疗靶点。这种干预可能通过减轻衰老和铁、胆固醇和自由基对少突胶质细胞及其髓磷脂的相关变化的影响，潜在地治疗多种退行性脑疾病。
The amyloid hypothesis (AH) of Alzheimer’s disease (AD) posits that the fundamental cause of AD is the accumulation of the peptide amyloid beta (Aβ) in the brain. This hypothesis has been supported by observations that genetic defects in amyloid precursor protein (APP) and presenilin increase Aβ production and cause familial AD (FAD). The AH is widely accepted but does not account for important phenomena including recent failures of clinical trials to impact dementia in humans even after successfully reducing Aβ deposits. Herein, the AH is viewed from the broader overarching perspective of the myelin model of the human brain that focuses on functioning brain circuits and encompasses white matter and myelin in addition to neurons and synapses. The model proposes that the recently evolved and extensive myelination of the human brain underlies both our unique abilities and susceptibility to highly prevalent age-related neuropsychiatric disorders such as late onset AD (LOAD). It regards oligodendrocytes and the myelin they produce as being both critical for circuit function and uniquely vulnerable to damage. This perspective reframes key observations such as axonal transport disruptions, formation of axonal swellings/sphenoids and neuritic plaques, and proteinaceous deposits such as Aβ and tau as by-products of homeostatic myelin repair processes. It delineates empirically testable mechanisms of action for genes underlying FAD and LOAD and provides “upstream” treatment targets. Such interventions could potentially treat multiple degenerative brain disorders by mitigating the effects of aging and associated changes in iron, cholesterol, and free radicals on oligodendrocytes and their myelin.
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影响因子：
10.6
作者：
Bartzokis, G;Nuechterlein, KH;Mintz, J
通讯作者：
Mintz, J
影响因子：
--
作者：
Bartzokis, G;Beckson, M;Mintz, J
通讯作者：
Mintz, J
影响因子：
6.4
作者：
Albert, Monika;Antel, Jack;Stadelmann, Christine
通讯作者：
Stadelmann, Christine
影响因子：
12.7
作者：
Aboul-Enein, F;Weiser, P;Bradl, M
通讯作者：
Bradl, M
影响因子：
12.7
作者：
Akiguchi, I;Tomimoto, H;Budka, H
通讯作者：
Budka, H