Investigation of T Cell-induced Neuroinflammation in Alzheimer’s Disease

Abstract Text: Previous studies have implicated T cells in the brains and CSF of Alzheimer’s disease (AD) patients. However, most studies are small and focus primarily on the hippocampus at later Braak stages, and little is known about their role over the course of the disease.
Informed by scRNAseq of immune cells isolated from fresh autopsies, we have investigated T cell frequencies and subtypes in the aging and AD brains. Namely, we compared T cell frequency in four brain regions affected by AD—entorhinal, prefrontal and posterior cortices, and hippocampus—across all Braak stages (from Braak 0 – minimal AD pathology - to Braak 6 - extensive pathology mixed with other neuropathologies) by automated segmentation and quantitative analysis of immunofluorescence (IF)-stained post-mortem brain tissue sections. We therefore characterize the phenotype and topology of T cells in their perivascular, parenchymal, and meningeal niches.
In the first 23 individuals (out of 100 being profiled), we found that T cell number is higher in the hippocampus compared to the other three regions but only at Braak stages 4 and 5 (reduced in Braak 6). A small number of CD8+ T cells in the AD brains exhibit tissue-resident traits, while some in the perivascular space are activated. Most interestingly, our data suggest that local inflammation might cause accumulation of granzyme K-secreting CD8+ T cells and C3 complement activation in AD brains. This study clarifies the timing and location of T cells in the course of AD: they do not anticipate but rather follow the spread of pathology.