Peripheral immune cell infiltration into the brain is a prominent feature in aging and various neurodegenerative diseases such as Alzheimer’s disease (AD). As AD progresses, CD8⁺ T cells infiltrate into the brain parenchyma, where they tightly associate with neurons and microglia. The functional properties of CD8⁺ T cells in the brain are largely unknown. To gain further insights into the putative functions of CD8⁺ T cells in the brain, we explored and compared the transcriptomic profile of CD8⁺ T cells isolated from the brain and blood of transgenic AD (APPswe/PSEN1dE9, line 85 [APP-PS1]) and age-matched wild-type (WT) mice. Brain CD8⁺ T cells of APP-PS1 and WT animals had similar transcriptomic profiles and substantially differed from blood circulating CD8⁺ T cells. The gene signature of brain CD8⁺ T cells identified them as tissue-resident memory (Trm) T cells. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis on the significantly upregulated genes revealed overrepresentation of biological processes involved in IFN-β signaling and the response to viral infections. Furthermore, brain CD8⁺ T cells of APP-PS1 and aged WT mice showed similar differentially regulated genes as brain Trm CD8⁺ T cells in mouse models with acute virus infection, chronic parasite infection, and tumor growth. In conclusion, our profiling of brain CD8⁺ T cells suggests that in AD, these cells exhibit similar adaptive immune responses as in other inflammatory diseases of the CNS, potentially opening the door for immunotherapy in AD. Visual Abstract Key Points Brain CD8⁺ T cells of aged WT and APP-PS1 mice are identified as Trm T cells. Upregulated genes of brain CD8⁺ cells are involved in type I IFN signaling.

The gut microbiome is involved in nutrient metabolism and produces metabolites that, via the gut–brain axis, signal to the brain and influence cognition. Human studies have so far had limited success in identifying early metabolic alterations linked to cognitive aging, likely due to limitations in metabolite coverage or follow-ups. Older persons from the Three-City population-based cohort who had not been diagnosed with dementia at the time of blood sampling were included, and repeated measures of cognition over 12 subsequent years were collected. Using a targeted metabolomics platform, we identified 72 circulating gut-derived metabolites in a case–control study on cognitive decline, nested within the cohort (discovery n = 418; validation n = 420). Higher serum levels of propionic acid, a short-chain fatty acid, were associated with increased odds of cognitive decline (OR for 1 SD = 1.40 (95% CI 1.11, 1.75) for discovery and 1.26 (1.02, 1.55) for validation). Additional analyses suggested mediation by hypercholesterolemia and diabetes. Propionic acid strongly correlated with blood glucose (r = 0.79) and with intakes of meat and cheese (r > 0.15), but not fiber (r = 0.04), suggesting a minor role of prebiotic foods per se, but a possible link to processed foods, in which propionic acid is a common preservative. The adverse impact of propionic acid on metabolism and cognition deserves further investigation.

Hippocampal neurogenesis (HN) occurs throughout the life course and is important for memory and mood. Declining with age, HN plays a pivotal role in cognitive decline (CD), dementia, and late-life depression, such that altered HN could represent a neurobiological susceptibility to these conditions. Pertinently, dietary patterns (e.g., Mediterranean diet) and/or individual nutrients (e.g., vitamin D, omega 3) can modify HN, but also modify risk for CD, dementia, and depression. Therefore, the interaction between diet/nutrition and HN may alter risk trajectories for these ageing-related brain conditions. Using a subsample (n = 371) of the Three-City cohort—where older adults provided information on diet and blood biobanking at baseline and were assessed for CD, dementia, and depressive symptomatology across 12 years—we tested for interactions between food consumption, nutrient intake, and nutritional biomarker concentrations and neurogenesis-centred susceptibility status (defined by baseline readouts of hippocampal progenitor cell integrity, cell death, and differentiation) on CD, Alzheimer’s disease (AD), vascular and other dementias (VoD), and depressive symptomatology, using multivariable-adjusted logistic regression models. Increased plasma lycopene concentrations (OR [95% CI] = 1.07 [1.01, 1.14]), higher red meat (OR [95% CI] = 1.10 [1.03, 1.19]), and lower poultry consumption (OR [95% CI] = 0.93 [0.87, 0.99]) were associated with an increased risk for AD in individuals with a neurogenesis-centred susceptibility. Increased vitamin D consumption (OR [95% CI] = 1.05 [1.01, 1.11]) and plasma γ-tocopherol concentrations (OR [95% CI] = 1.08 [1.01, 1.18]) were associated with increased risk for VoD and depressive symptomatology, respectively, but only in susceptible individuals. This research highlights an important role for diet/nutrition in modifying dementia and depression risk in individuals with a neurogenesis-centred susceptibility.

Background/Objectives: Neuroinflammation, a hallmark of Alzheimer’s disease (AD), is characterized by elevated levels of inflammatory signaling molecules, including cytokines and eicosanoids, as well as increased microglial reactivity, and is augmented by gut microbiota dysbiosis via the gut–brain axis. We conducted a pilot experiment to elucidate the anti-inflammatory effects of dietary omega-3 polyunsaturated fatty acid (ω-3 PUFA) eicosapentaenoic acid (EPA) on the gut microbiota and neuroinflammation. Methods: Female APP/PS1 mice (TG) and non-transgenic littermates (WT), 13–14 months old, were fed a diet supplemented with 0.3% EPA or control chow for 3 weeks. The gut microbiota composition, hippocampal and plasma eicosanoids levels, platelet activation, and microglial phagocytosis, as well as the brain and retinal genes and protein expression, were analyzed. Results: EPA supplementation decreased the percentage of Bacteroidetes and increased bacteria of the phylum Firmicutes in APP/PS1 and WT mice. Inflammatory lipid mediators were elevated in the hippocampus of the TG mice, accompanied by a reduction in the endocannabinoid docosahexaenoyl ethanolamide (DHEA). Dietary EPA did not affect hippocampal lipid mediators, but reduced the levels of arachidonic-derived 5-HETE and N-arachidonoylethanolamine (AEA) in WT plasma. Moreover, EPA supplementation decreased major histocompatibility complex class II (MHCII) gene expression in the retina in both genotypes, and MHCII+ cells in the hippocampus of TG mice. Conclusions: This pilot study showed that short-term EPA supplementation shaped the gut microbiota by increasing butyrate-producing bacteria of the Firmicutes phylum and decreasing Gram-negative LPS-producing bacteria of the Bacteroidetes phylum, and downregulated the inflammatory microglial marker MHCII in two distinct regions of the central nervous system (CNS). Further investigation is needed to determine whether EPA-mediated effects on the microbiome and microglial MHCII have beneficial long-term effects on AD pathology and cognition.

Alzheimer’s disease (AD) progression has been associated with the presence of brain-resident CD8 ⁺ T cells, and recent studies suggest a potential role of the CXCL16-CXCR6 axis in their recruitment to the brain. Here, we examined publicly available single-cell RNA sequencing datasets revealing that in the mouse brain, the receptor Cxcr6 is mainly expressed by CD8 ⁺ T cells, while the expression of its ligand Cxcl16 is predominantly observed in microglial cells. We found higher levels of Cxcl16 and Cxcr6 expression in APP/PS1 compared to wild-type mice. Furthermore, in vitro experiments using immortalized and primary murine cells suggested that Cxcl16 expression is driven by Aβ pathology. In contrast to our expectations, no changes in the number of Cxcr6 ⁺ CD8 ⁺ cells was evident in the brains of microglia-depleted APP/PS1 mice, treated with the CSF1R antagonist PLX5622. This was related to an increased compensatory Cxcl16 expression by depletion-resistant microglia or by other brain-resident myeloid cells. Although we demonstrated a strong association between microglial Cxcl16 and AD pathology, PLX5622-sensitive microglia are dispensable in the recruitment of Cxcr6 ⁺ CD8 ⁺ T cells to the brain of APP/PS1 mice. Future in vivo analysis will help to dissect the mechanism of CD8 ⁺ T cell recruitment to the brain.

CD8⁺ T cells infiltrate the brain parenchyma of patients with Alzheimer’s disease (AD), where they localize near microglia and neurons. Although recent studies have revealed that they can clonally expand and possess a unique phenotype, their contribution to disease pathogenesis remains poorly understood. To investigate the role of these cells in AD, we first performed exploratory immunopeptidome profiling in aged transgenic AD (APP/PS1) mice to identify potential major histocompatibility complex class I-presented antigens that might drive CD8⁺ T cell recruitment. Surprisingly, no peptides were found to be overrepresented in transgenic compared with control brains, suggesting the absence of a dominant antigenic signature. We next characterized brain-infiltrating CD8⁺ T cells by flow cytometry and found that, in aged APP/PS1 mice, these cells exhibit a tissue-resident phenotype distinct from their circulating counterparts. To assess their functional relevance, we induced short-term CD8⁺ T cell depletion in two-year-old APP/PS1 mice using anti-CD8 antibody injections over three days and subsequently analyzed brain pathology and gene expression. CD8⁺ T cell depletion effectively reduced CD8⁺ T cell numbers in both blood and brain. Although amyloid plaque burden remained unchanged, female mice showed reduced LAMP1 ⁺ dystrophic neurites surrounding plaques and decreased phosphorylated tau deposition. These effects were accompanied by a modest increase in microglial abundance and elevated hippocampal Il1b expression. Collectively, these findings indicate that brain-resident CD8⁺ T cells contribute to specific aspects of AD-related neurodegeneration in a potential sex-dependent manner (although further experiments are needed), supporting a previously underappreciated role for CD8⁺ T cells in AD progression.