The role of non-neuronal cells in Alzheimer’s disease (AD) progression has not been fully elucidated. Using single-nucleus RNA-seq, we identified a population of disease associated astrocytes (DAAs) in an AD mouse model. The DAA population appeared at early disease stages and increased in abundance with age. We discovered that similar astrocytes appeared in aged wild-type mice and in aging human brains, suggesting their linkage to genetic and age-related factors.
Systemic immunity supports lifelong brain function. Obesity posits a chronic burden on systemic immunity. Independently, obesity was shown as a risk factor for Alzheimer’s disease (AD). Here we show that high-fat obesogenic diet accelerated recognition-memory impairment in an AD mouse model (5xFAD). In obese 5xFAD mice, hippocampal cells displayed only minor diet-related transcriptional changes, whereas the splenic immune landscape exhibited aging-like CD4+ T-cell deregulation. Following plasma metabolite profiling, we identified free N-acetylneuraminic acid (NANA), the predominant sialic acid, as the metabolite linking recognition-memory impairment to increased splenic immune-suppressive cells in mice. Single-nucleus RNA-sequencing revealed mouse visceral adipose macrophages as a potential source of NANA. In vitro, NANA reduced CD4+ T-cell proliferation, tested in both mouse and human. In vivo, NANA administration to standard diet-fed mice recapitulated high-fat diet effects on CD4+ T cells and accelerated recognition-memory impairment in 5xFAD mice. We suggest that obesity accelerates disease manifestation in a mouse model of AD via systemic immune exhaustion.
Systemic immunity supports healthy brain homeostasis. Accordingly, conditions causing systemic immune deregulation may accelerate onset of neurodegeneration in predisposed individuals. Here we show that, in the 5xFAD mouse model of Alzheimer's disease (AD), high-fat diet-induced obesity accelerated cognitive decline, which was associated with immune deviations comprising increased splenic frequencies of exhausted CD4+ T effector memory cells and CD4+FOXP3+ regulatory T cells (Tregs). Non-targeted plasma metabolomics identified N-acetylneuraminic acid (NANA), the predominant sialic acid, as the major obesity-induced metabolite in 5xFAD mice, the levels of which directly correlated with Tregs abundance and inversely correlated with cognitive performance. Visceral adipose tissue macrophages were identified by sNuc-Seq as one potential source of NANA. Exposure to NANA led to immune deregulation in middle-aged wild-type mice, and ex vivo in human T cells. Our study identified diet-induced immune deregulation, potentially via sialic acid, as a previously unrecognized link between obesity and AD.
El presente estudio tuvo como objetivo evaluar el efecto de la aplicación de plasma seminal, un análogo de GnRH y la ablación folicular sobre la dinámica folicular en llamas. El estudio se realizó en Puno, Perú, utilizando 24 llamas seleccionadas bajo el criterio de presentar un folículo preovulatorio >7 mm, determinado mediante ecografía transrectal. Las llamas fueron distribuidas aleatoriamente en cuatro grupos: T1, 1 ml PBS IM; T2, 2 ml plasma seminal IM; T3, 1 ml GnRH IM; T4, ablación folicular. Los animales fueron evaluados, mediante ecografía transrectal, cada 2 h entre las 20 hasta las 36 h post-tratamiento para determinar la ovulación; posteriormente en forma diaria hasta el día 9 y luego cada 2 días hasta el día 15 pos-estímulo para determinar el intervalo a la emergencia de una nueva onda folicular, la aparición del nuevo folículo dominante y el diámetro del cuerpo lúteo al día 8 del tratamiento. No se encontró diferencia significativa (p<0.05) entre tratamientos en las variables en estudio. Es posible que existan otros factores que podrían afectar el intervalo a la emergencia de una nueva onda folicular.
Dementia in general, and Alzheimer's disease (AD) in particular, are age-related diseases (1,2). AD is associated with multiple causative factors (3,4), among which local brain inflammation plays a significant role (5). Microglia, the brain-resident immune cells, are activated along the disease course (6,7). Yet, their contribution to the disease progression is still controversial. Here, using high-throughput mass cytometry for microglial immuno-phenotyping, we identified accumulation of senescent microglia in several pathologies associated with cognitive decline. These senescent microglia have a unique profile conserved across the multiple conditions investigated, including aging, mouse models of amyloidosis, and tauopathy. Moreover, we found that the expression of markers of senescence correlates with levels of TREM2, whose polymorphism was identified by GWAS as an AD risk factor (8,9). A TREM2-null AD mouse model showed lower levels of senescent microglia, relative to TREM2-intact AD mice. Senolysis using the drug ABT-73710,11 in an AD mouse model reduced the abundance of TREM2-senescent microglia without affecting levels of TREM2-dependent activated microglia, ameliorated cognitive deficits, and reduced brain inflammation. These results reveal the unexpected contribution of TREM2 to accumulation of senescent microglia in AD pathology, an effect that must be considered when targeting TREM2 as a therapeutic approach.
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