T Cells Actively Infiltrate the White Matter of the Aging Monkey Brain in Relation to Increased Microglial Reactivity and Cognitive Decline.
T Cells Actively Infiltrate the White Matter of the Aging Monkey Brain in Relation to Increased Microglial Reactivity and Cognitive Decline.
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DOI：
10.3389/fimmu.2021.607691
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发表时间：
2021
影响因子：
7.3
通讯作者：
Rosene DL
中科院分区：
文献类型：
--
作者：
Batterman KV;Cabrera PE;Moore TL;Rosene DL
正常衰老的特征是处理速度、学习、记忆和执行功能下降，即使没有阿尔茨海默病（AD）等神经退行性疾病也是如此。在正常衰老的猴子和人类中，神经元的丧失并不能解释认知障碍。相反，白色物质体积的损失和髓鞘病理学的积累开始于中年，并与认知能力下降相关。目前尚不清楚是什么原因导致这种髓鞘病变，但它可能涉及白色物质中神经炎症的增加和少突胶质细胞功能（成熟和修复）的失败。在易受髓鞘损伤的额叶白色物质束中，小胶质细胞变得慢性反应并分泌有害的促炎细胞因子。尽管处于吞噬状态，这些小胶质细胞在吞噬积累的髓鞘碎片方面是无效的，这直接抑制髓鞘修复。在这里，我们询问了促炎标志物中与年龄相关的增加是否伴随着涉及T细胞的适应性免疫反应。我们用免疫组织化学定量了34只具有认知特征的猴子大脑中的T细胞，发现围绕CNS血管的血管周围T细胞的年龄相关性增加。我们发现了一个令人惊讶的与年龄相关的T细胞浸润的白色实质的增加。在扣带束中，这些实质T细胞的百分比随着年龄的增长而增加，相对于血管周围空间中的那些。相反，在周围灰质区域很少发现浸润性T细胞。我们评估了T细胞浸润是否与纤维蛋白原从血管外渗相关，作为BBB渗漏的测量，没有发现相关性，表明T细胞浸润不是被动外渗的结果。重要的是，扣带束中T细胞的密度与小胶质细胞反应性和认知障碍相关。这是第一次证明白色物质的T细胞浸润与正常衰老猴子的认知能力下降有关。
Normal aging is characterized by declines in processing speed, learning, memory, and executive function even in the absence of neurodegenerative diseases such as Alzheimer's Disease (AD). In normal aging monkeys and humans, neuronal loss does not account for cognitive impairment. Instead, loss of white matter volume and an accumulation of myelin sheath pathology begins in middle age and is associated with cognitive decline. It is unknown what causes this myelin pathology, but it likely involves increased neuroinflammation in white matter and failures in oligodendrocyte function (maturation and repair). In frontal white matter tracts vulnerable to myelin damage, microglia become chronically reactive and secrete harmful pro-inflammatory cytokines. Despite being in a phagocytic state, these microglia are ineffective at phagocytosing accruing myelin debris, which directly inhibits myelin sheath repair. Here, we asked whether reported age-related increases in pro-inflammatory markers were accompanied by an adaptive immune response involving T cells. We quantified T cells with immunohistochemistry in the brains of 34 cognitively characterized monkeys and found an age-related increase in perivascular T cells that surround CNS vasculature. We found a surprising age-related increase in T cells that infiltrate the white matter parenchyma. In the cingulum bundle the percentage of these parenchymal T cells increased with age relative to those in the perivascular space. In contrast, infiltrating T cells were rarely found in surrounding gray matter regions. We assessed whether T cell infiltration correlated with fibrinogen extravasation from the vasculature as a measure of BBB leakiness and found no correlation, suggesting that T cell infiltration is not a result of passive extravasation. Importantly, the density of T cells in the cingulum bundle correlated with microglial reactivity and with cognitive impairment. This is the first demonstration that T cell infiltration of white matter is associated with cognitive decline in the normal aging monkey.
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影响因子：
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作者：
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DOI：
10.1126/science.1252945
发表时间：
2014-10-03
期刊：
Science (New York, N.Y.)
影响因子：
--
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