Tau Post-Translational Modifications: Potentiators of Selective Vulnerability in Sporadic Alzheimer's Disease.
Tau Post-Translational Modifications: Potentiators of Selective Vulnerability in Sporadic Alzheimer's Disease.
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DOI：
10.3390/biology10101047
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发表时间：
2021-10-15
期刊：
影响因子：
4.2
通讯作者：
Johnson GVW
中科院分区：
文献类型：
--
作者：
Carroll T;Guha S;Nehrke K;Johnson GVW
大多数阿尔茨海默病（AD）病例的空间进展遵循一个明确的通过大脑的路径，但对该疾病的研究尚未确定为什么会发生这种特定的疾病进展模式。最近的发展表明，某些神经元比其他神经元更容易受到AD应激的影响，这一概念后来被称为“选择性脆弱性”。确定使某些神经元更容易受到疾病影响的细胞机制可以为疾病如何导致神经退行性变并最终导致痴呆症提供重要见解。这篇综述探讨了tau蛋白的修饰，AD发病机制的关键介质，可能有助于选择性的脆弱性，并确定可能参与疾病进展的最早阶段的关键细胞成分。散发性阿尔茨海默病（AD）是痴呆的最常见形式，并且其严重性的特征在于tau神经元缠结沿着通过脑的充分描述的路径的进行性形成。这种空间进展为AD病理进展的Braak分期提供了基础。Tau蛋白是AD病理学的必要组成部分，最近的研究发现，在AD相关的不溶性聚集体形成之前，具有选择性但非广泛修饰的表位的可溶性Tau种类沿着疾病进展的路径积累。因此，修饰的tau蛋白可能代表了一种关键的细胞应激剂，其在AD进展期间增强易感神经元的选择性脆弱性。具体而言，研究发现，在诸如T181、T231和S396的位点磷酸化的tau可以通过破坏适当的tau定位、启动tau寡聚化和促进tau积累和细胞外输出来启动tau的早期病理变化。因此，本综述阐明了tau蛋白翻译后修饰（PTM）可能同时作为AD发展中观察到的空间进展的关键调节剂和与神经退行性疾病相关的细胞功能障碍相关的早期病理学的关键煽动者的潜在机制。
The spatial progression of most Alzheimer’s Disease (AD) cases follows a well-defined route through the brain, yet research on the disease has yet to determine why this specific pattern of disease progression occurs. Recent developments have revealed that certain neurons are more vulnerable to AD stress than others, a concept which has since been termed “selective vulnerability”. Determining the cellular mechanisms that make certain neurons more vulnerable to disease could provide critical insights into how the disease leads to neurodegeneration and ultimately causes dementia. This review explores how modification of tau protein, a critical mediator of AD pathogenesis, may contribute to selective vulnerability and identifies key cellular components that may be involved at the earliest stages of disease progression. Sporadic Alzheimer’s Disease (AD) is the most common form of dementia, and its severity is characterized by the progressive formation of tau neurofibrillary tangles along a well-described path through the brain. This spatial progression provides the basis for Braak staging of the pathological progression for AD. Tau protein is a necessary component of AD pathology, and recent studies have found that soluble tau species with selectively, but not extensively, modified epitopes accumulate along the path of disease progression before AD-associated insoluble aggregates form. As such, modified tau may represent a key cellular stressing agent that potentiates selective vulnerability in susceptible neurons during AD progression. Specifically, studies have found that tau phosphorylated at sites such as T181, T231, and S396 may initiate early pathological changes in tau by disrupting proper tau localization, initiating tau oligomerization, and facilitating tau accumulation and extracellular export. Thus, this review elucidates potential mechanisms through which tau post-translational modifications (PTMs) may simultaneously serve as key modulators of the spatial progression observed in AD development and as key instigators of early pathology related to neurodegeneration-relevant cellular dysfunctions.
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