PDF(Pubmed)
Abstract：
Cortical neuron loss is a pathological hallmark of late-onset Alzheimer\'s disease (AD). However, it remains unclear which neuronal subtypes beyond broad excitatory and inhibitory classes are most vulnerable. Here, we analyzed cell subtype proportion differences in AD compared to non-AD controls using 1037 post-mortem brain samples from six neocortical regions. We identified the strongest associations of AD with fewer somatostatin (SST) inhibitory neurons (β = -0.48, p bonf = 8.98 × 10-9) and intra-telencephalic (IT) excitatory neurons (β = -0.45, p bonf = 4.32 × 10-7). Replication in three AD case-control single-nucleus RNAseq datasets most strongly supported the bulk tissue association of fewer SST neurons in AD. In depth analyses of cell type proportions with specific AD-related neuropathological and cognitive phenotypes revealed fewer SST neurons with greater brain-wide post-mortem tau and beta amyloid, as well as a faster rate of antemortem cognitive decline. In contrast, greater IT neuron proportions were associated with a slower rate of cognitive decline as well as greater residual cognition-a measure of cognitive resilience-but not canonical AD neuropathology. Our findings implicate somatostatin inhibitory and intra-telencephalic excitatory neuron subclasses in the pathogenesis of AD and in cognitive resilience to AD pathology, respectively.
摘要：
皮质神经元丢失是晚发性阿尔茨海默病(AD)的病理标志。然而,目前尚不清楚广泛的兴奋性和抑制性以外的哪些神经元亚型最脆弱.这里,我们使用来自6个新皮质区域的1037个死后脑样本,分析了AD与非AD对照的细胞亚型比例差异.我们确定了AD与生长抑素（SST）抑制性神经元（β=-0.48，pbonf=8.98×10-9）和端脑（IT）兴奋性神经元（β=-0.45，pbonf=4.32×10-7）的最强关联。在三个AD病例对照单核RNAseq数据集中的复制最强烈地支持AD中较少SST神经元的整体组织关联。对具有特定AD相关神经病理学和认知表型的细胞类型比例的深入分析显示，SST神经元较少，死后全脑tau和β淀粉样蛋白更大，以及更快的死前认知衰退速度。相比之下,更高的IT神经元比例与更慢的认知下降速度以及更大的残余认知相关-认知弹性的量度-但与规范的AD神经病理学无关.我们的发现暗示生长抑素抑制性和脑内兴奋性神经元亚类在AD的发病机理和对AD病理的认知弹性中。分别。
