PDF(Pubmed)
Abstract：
Cerebral (Aβ) plaque and (pTau) tangle deposition are hallmarks of Alzheimer\'s disease (AD), yet are insufficient to confer complete AD-like neurodegeneration experimentally. Factors acting upstream of Aβ/pTau in AD remain unknown, but their identification could enable earlier diagnosis and more effective treatments. T cell abnormalities are emerging AD hallmarks, and CD8 T cells were recently found to mediate neurodegeneration downstream of tangle deposition in hereditary neurodegeneration models. The precise impact of T cells downstream of Aβ/pTau, however, appears to vary depending on the animal model. Our prior work suggested that antigen-specific memory CD8 T (\"hiT\") cells act upstream of Aβ/pTau after brain injury. Here, we examine whether hiT cells influence sporadic AD-like pathophysiology upstream of Aβ/pTau. Examining neuropathology, gene expression, and behavior in our hiT mouse model we show that CD8 T cells induce plaque and tangle-like deposition, modulate AD-related genes, and ultimately result in progressive neurodegeneration with both gross and fine features of sporadic human AD. T cells required Perforin to initiate this pathophysiology, and IFNγ for most gene expression changes and progression to more widespread neurodegenerative disease. Analogous antigen-specific memory CD8 T cells were significantly elevated in the brains of human AD patients, and their loss from blood corresponded to sporadic AD and related cognitive decline better than plasma pTau-217, a promising AD biomarker candidate. We identify an age-related factor acting upstream of Aβ/pTau to initiate AD-like pathophysiology, the mechanisms promoting its pathogenicity, and its relevance to human sporadic AD.
摘要：
脑（Aβ）斑块和（pTau）缠结沉积是阿尔茨海默病（AD）的标志，然而，不足以通过实验赋予完全的AD样神经变性。AD中Aβ/pTau上游的作用因素尚不清楚，但是他们的鉴定可以实现更早的诊断和更有效的治疗。T细胞异常是新出现的AD标志，最近发现CD8T细胞在遗传性神经变性模型中介导缠结沉积下游的神经变性。Aβ/pTau下游T细胞的精确影响，然而,似乎取决于动物模型。我们先前的工作表明，脑损伤后，抗原特异性记忆CD8T（“hiT”）细胞在Aβ/pTau上游起作用。这里,我们检查hiT细胞是否影响Aβ/pTau上游的散发性AD样病理生理学。检查神经病理学，基因表达，在我们的hiT小鼠模型中，我们显示CD8T细胞诱导斑块和缠结样沉积，调节AD相关基因，并最终导致具有散发性人类AD的总体和精细特征的进行性神经变性。T细胞需要穿孔素来启动这种病理生理学，和IFNγ用于大多数基因表达变化和进展为更广泛的神经退行性疾病。类似的抗原特异性记忆CD8T细胞在人类AD患者的大脑中显著升高，与血浆pTau-217(一种有前途的AD生物标志物候选物)相比,他们的血液损失与散发性AD和相关认知能力下降相对应。我们确定了在Aβ/pTau上游起作用以启动AD样病理生理学的年龄相关因素，促进其致病性的机制，及其与人类散发性AD的相关性。
