Glial reactivity and T cell infiltration in frontotemporal lobar degeneration with tau pathology

Abstract Frontotemporal lobar degeneration with tau (FTLD-tau) is a group of tauopathies that underlie ∼50% of frontotemporal lobar degeneration (FTLD) cases. Identification of genetic risk variants related to innate/adaptive immunity have highlighted a role for neuroinflammation and neuroimmune interactions in FTLD. Studies have shown microglial and astrocyte activation together with T cell infiltration in the brain of THY-Tau22 tauopathy mice. However, this remains to be confirmed in FTLD-tau patients. We conducted a detailed post-mortem study of FTLD-Tau cases including 45 Progressive Supranuclear Palsy (PSP) with clinical frontotemporal dementia, 33 Pick’s Disease (PiD), 12 FTLD-MAPT and 52 controls to characterise the link between phosphorylated tau (pTau) epitopes and the innate and adaptive immunity. Tau pathology was assessed in the cerebral cortex using antibodies directed against: Tau-2 (phosphorylated and unphosphorylated tau), AT8 (pSer202/pThr205), AT100 (pThr212/pSer214), CP13 (pSer202), PHF1(pSer396/pSer404), pThr181 and pSer356. The immunophenotypes of microglia and astrocytes were assessed with phenotypic markers (Iba1, CD68, HLA-DR, CD64, CD32a, CD16 for microglia and GFAP, EAAT2, Glutamine Synthetase and ALDH1L1 for astrocytes). The adaptive immune response was explored via CD4+ and CD8+ T cells quantification, and the neuroinflammatory environment was investigated via the expression of 30 inflammatory-related proteins using V-Plex Meso Scale Discovery. As expected, all pTau markers were increased in FTLD-Tau cases compared to controls. pSer356 expression was greatest in FTLD-MAPT cases vs. controls (P < 0.0001), whereas the expression of other markers was highest in PiD. PSP with FTD consistently had a lower pTau protein load compared to PiD across tau epitopes. The only microglial marker increased in FTLD-Tau was CD16 (P = 0.0292) and specifically in FTLD-MAPT cases (P = 0.0150). However several associations were detected between pTau epitopes and microglia, supporting an interplay between them. GFAP expression was increased in FTLD-Tau (P = 0.0345) with the highest expression in PiD (P = 0.0019), while ALDH1L1 was unchanged. Markers of astrocyte glutamate cycling function were reduced in FTLD-tau (P = 0.0075; PiD: P < 0.0400) implying astrocyte reactivity associated with a decreased glutamate cycling activity which was further associated with pTau expression. Of the inflammatory proteins assessed in the brain, five chemokines were upregulated in PiD cases (P < 0.0400), consistent with the recruitment of CD4+ (P = 0.0109) and CD8+ (P = 0.0014) T cells. Of note, the CD8+ T cell infiltration was associated with pTau epitopes and microglial and astrocytic markers. Our results highlight that FTLD-tau is associated with astrocyte reactivity, remarkably little activation of microglia, but involvement of adaptive immunity in the form of chemokine-driven recruitment of T lymphocytes.