Short-Term CD8+ T Cell Depletion Alters Tau Pathology in Aged Alzheimer’s Model Mice

CD8+ T cells, immune cells best known for killing infected or abnormal cells, have been found inside the brains of patients with Alzheimer’s disease, where they gather near microglia and neurons. A new study in aged transgenic APP/PS1 mice, which carry amyloid precursor protein and presenilin mutations used to model Alzheimer-like pathology, now reports what happens when these cells are briefly removed. The work, published as an open-access original research article in Cellular and Molecular Neurobiology, suggests that brain-resident CD8+ T cells contribute to specific aspects of Alzheimer-related neurodegeneration, potentially in a sex-dependent manner.

CD8+ T cells recognize short peptides presented on major histocompatibility complex class I molecules at the surface of cells. The investigators therefore performed exploratory immunopeptidome profiling in aged APP/PS1 mice, cataloguing the MHC class I-presented peptides in transgenic brains compared with control brains.

The result was unexpected. No peptides were overrepresented in the transgenic animals, indicating the absence of a dominant antigenic signature that could explain CD8+ T cell recruitment. This null finding is itself informative, because it argues against a simple model in which a single abundant brain-derived antigen drives the accumulation of these immune cells in the Alzheimer’s brain. The authors note that the contribution of CD8+ T cells to disease pathogenesis remains poorly understood, even though recent studies have shown that brain-infiltrating CD8+ T cells in AD can clonally expand and display a unique phenotype.

Next, the team characterized the brain-infiltrating CD8+ T cells by flow cytometry. In aged APP/PS1 mice, these cells exhibited a tissue-resident phenotype distinct from their circulating counterparts in the blood. Tissue-resident memory T cells persist within an organ rather than patrolling the bloodstream, and this distinction matters for interpreting the depletion experiment that followed: the cells being targeted were not merely passing visitors but cells embedded in the brain environment.

To test whether these resident cells influence disease pathology, the researchers induced short-term CD8+ T cell depletion in two-year-old APP/PS1 mice using anti-CD8 antibody injections over three days, then analyzed brain pathology and gene expression. The depletion worked as intended, reducing CD8+ T cell numbers in both blood and brain. The brief treatment window is a key design feature: rather than eliminating the cells for the animal’s lifetime, the experiment asked what acute, near-term consequences follow when the cells are removed in animals that already carry extensive AD-like pathology.

The pathological readouts split in an instructive way. Amyloid plaque burden, the hallmark accumulation of amyloid-beta that gives APP/PS1 mice their name, remained unchanged after depletion. However, in female mice, two downstream markers of neurodegeneration shifted: the animals showed reduced LAMP1-positive dystrophic neurites surrounding plaques, a measure of damaged and swollen nerve fibers near amyloid deposits, and decreased deposition of phosphorylated tau, the abnormal tau modification that defines another hallmark of Alzheimer’s disease.

Accompanying these changes, the depleted female mice displayed a modest increase in microglial abundance and elevated hippocampal expression of Il1b, a gene encoding the pro-inflammatory cytokine interleukin-1 beta. The direction of this immune shift is not straightforward to interpret. More microglia and higher inflammatory gene expression could reflect altered regulation of the brain’s innate immune compartment once the adaptive CD8+ component is removed, and the study did not establish a causal chain linking these gene-expression changes to the reductions in neurite damage and tau phosphorylation.

The authors are careful about scope. They describe the sex-dependent pattern as potential, explicitly stating that further experiments are needed, and the depletion effects on neurites and tau were observed in female mice within this dataset. The findings are also confined to a single transgenic mouse model at an advanced age, with a short depletion protocol and exploratory immunopeptidomics that detected no dominant antigen. What the study does establish is a previously underappreciated role for CD8+ T cells in AD progression: removing brain-resident CD8+ T cells for just three days leaves amyloid untouched but measurably alters tau-related and neuritic pathology in aged female APP/PS1 mice, pointing to these immune cells as active participants in specific degenerative processes rather than passive bystanders.

Subject of Research: The role of brain-resident CD8+ T cells in Alzheimer-related pathology in aged APP/PS1 mice

Article Title: The Impact of a Short-Term Reduction in CD8+ T Cells on Aged APP/PS1 Mice

Article References: Zattoni, M., Bernegger, S., Mrowetz, H., Weinbender, S. C., Rieder, S.-M., Maksimovic, M., Altendorfer, B., Benedetti, A., Forster, J., Unger, M. S., Asslaber, D., Egle, A., Becker, J. P., Riemer, A. B., & Aigner, L. (2026). The Impact of a Short-Term Reduction in CD8+ T Cells on Aged APP/PS1 Mice. Cellular and Molecular Neurobiology. https://doi.org/10.1007/s10571-026-01832-5

Image Credits: AI Generated

DOI: 10.1007/s10571-026-01832-5

Keywords: Alzheimer's disease, CD8+ T cells, APP/PS1 mice, tau pathology, microglia, immunopeptidomics, neuroimmunology, tissue-resident T cells, amyloid plaques, sex-dependent effects, Impact, Short-Term