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Granzyme K+ CD8 T cells slow tauopathy progression by targeting microglia c

ABSTRACT: Neurodegenerative diseases trigger innate and adaptive immune responses that can either slow or accelerate disease progression. How immune cells contribute to such divergent disease outcomes is not entirely clear. Here, we sought to define beneficial immune pressure that emerged during development of tauopathies in mice and humans. Using mice that express mutant human tau in neurons, we observed that microglia slowed tauopathy development by controlling the spread of tau throughout the CNS and into the blood. However, over time microglia converted into distressed antigen presenting cells, acquired neuronal transcripts, and were targeted by resident CD8+ T cells. We detected clonally expanded CD8+ T cells in the CNS and draining lymph nodes of tauopathy mice that expressed granzyme K, but not traditional effector molecules (e.g., IFN, TNF, granzymes a/b/c), which was deposited onto the microglia they targeted. In fact, engagement of microglia by granzyme K expressing CD8+ T cells was a signature of tauopathy development in mice as well as humans with tau rich brain lesions linked to age, Alzheimer’s disease, or chronic traumatic encephalopathy. Deletion of CD8+ T cells in mice promoted the appearance of distressed microglia containing neuronal transcripts, markedly enhanced tau spread, and accelerated neurological decline. These data highlight a beneficial immune reaction involving microglia and granzyme K expressing CD8+ T cells that can slow tauopathy progression. Enhancement of this coordinated response offers the potential to improve outcomes in tauopathy patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE273757 | GEO | 2025/06/20

REPOSITORIES: GEO

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Project description:Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by the buildup of amyloid-β and tau protein tangles. Alcohol use has been identified as a risk factor for AD; however, the molecular mechanisms underlying this potential causal link remain elusive. An emerging area of research focuses on the role of microglia, the brain's innate immune cells, in AD pathogenesis, with evidence suggesting that alcohol exposure may prime microglia to exhibit an exaggerated immune response when they are subsequently exposed to proinflammatory stimuli. We used a single 10-day chronic-plus-binge alcohol exposure model in male and female C57BL/J mice aged 8- to 10-weeks old. One month later, tauopathy was induced via adenoviral vector (AAV)-mediated overexpression of h-p301L tau. After 2.5 months, the mice underwent behavioral and cognitive testing. Two weeks later, microglia were collected using fluorescence-activated cell sorting (FACS) and processed for unbiased mass spectrometry and deep proteomic analysis to determine the molecular pathways related to microglial reactivity. Microglia from mice exposed to alcohol in young adulthood exhibited a blunted immune response when challenged with AAV-mediated delivery and accumulation of human tau later in life. This was characterized by decreased expression of MHC II- and interferon-associated proteins and bioinformatic prediction of inhibited inflammation-related pathways in the absence of gross histological, behavioral, or cognitive deficits. These results demonstrate unique, temporally specific microglial reactivity to tau that is modulated by early life alcohol exposure, implicating a microglial response that could negatively affect the mechanisms necessary for tau clearance and potentially exacerbate tau pathogenesis. This study provides novel insights into the long-term effects of early alcohol exposure on microglial function and the complexity of context-dependent microglial involvement in tau pathology. Consideration of early life environmental factors is critical for understanding and potentially mitigating the risk of neurodegenerative diseases, such as AD.

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Granzyme K+ CD8 T cells slow tauopathy progression by targeting microglia c

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