Project description:Recent evidence suggests an important role of the gut microbiome in early life on immune cell entraining. Using two independent transgenic (Tg) lines of Alzheimer’s disease, we have demonstrated that life-long antibiotic (ABX)-perturbation of the gut microbiome is associated with reduced amyloid beta (Ab) plaque pathology and microglial phenotypes in male mice. Furthermore, fecal microbiota transfer (FMT) from age-matched APPPS1-21 Tg mice into long-term ABX-treated male APPPS1-21 mice partially restored amyloidosis and microgliosis, thus establishing causality. in the current studies, we planned to investigate the transcriptome profiles in APPPS1-21 mice treated with short-term abx (PND14-21) compared with vehicle treated groups in genotype-, sex- and time -dependent manner. Most importantly, we also investigated if fecal microbiota transplants from age-matched Tg male mice into short-term abx (PND14-21)-treated male mice restores brain transcriptomes to that of obsreved in vehicle-treated male mice at 9 weeks of age.
Project description:Age-related myelin damage induces inflammatory responses, yet its involvement in Alzheimer’s disease (AD) remains uncertain, despite age being a major risk factor. Using a mouse model of AD, we found that amyloidosis itself triggers age-related oligodendrocyte and myelin damage. Mechanistically, CD8+ T cells promote the progressive accumulation of abnormally interferon-activated microglia that display myelin-damaging activity. Thus, immune responses against myelinating oligodendrocytes may contribute to neurodegenerative diseases with amyloidosis.
Project description:Age-related myelin damage induces inflammatory responses, yet its involvement in Alzheimer's disease remains uncertain, despite age being a major risk factor. Using a mouse model of Alzheimer's disease, we found that amyloidosis itself triggers age-related oligodendrocyte and myelin damage. Mechanistically, CD8+ T cells promote the progressive accumulation of abnormally interferon-activated microglia that display myelin-damaging activity. Thus, our data suggest that immune responses against myelinating oligodendrocytes may contribute to neurodegenerative diseases with amyloidosis.
Project description:Age-associated microglial dysfunction contributes to the accumulation of amyloid-b (Ab) plaques in Alzheimer’s disease. Although several studies have shown age-related declines in the phagocytic capacity of myeloid cells, relatively few have examined phagocytosis of normally aged microglia. Furthermore, much of the existing data on aging microglial function have been generated in accelerated genetic models of Alzheimer’s disease. Here we found that naturally aged microglia phagocytosed less Ab over time. To gain a better understanding of such dysfunction, we assessed differences in gene expression between young and old microglia that either did or did not phagocytose Ab. Young microglia had both phagocytic and neuronal maintenance signatures indicative of normal microglial responses, whereas, old microglia, regardless of phagocytic status, exhibit signs of broad dysfunction reflective of underlying neurologic disease states. We also found downregulation of many phagocytic receptors on old microglia, including TREM2, an Ab phagocytic receptor. TREM2 protein expression was diminished in old microglia and loss of TREM2+ microglia was correlated with impaired Ab uptake, suggesting a mechanism for phagocytic dysfunction in old microglia. Combined, our work reveals that normally aged microglia have broad changes in gene expression, including defects in Ab phagocytosis that likely underlies the progression to neurologic disease.
Project description:Exercise interventions are beneficial for reducing the risk of age-related diseases, including amyloidosis, but the underlying molecular links remain unelucidated. Here, we investigated the protective role of interval exercise training in a mouse model of age-related systemic apolipoprotein A-II amyloidosis (AApoAII) and elucidated potential mechanisms. Mice subjected to sixteen weeks of exercise improved whole-body physiologic functions and exhibited substantial inhibition of amyloidosis, particularly in the liver and spleen. Exercise activated the hepatic p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway and the downstream transcription factor tumor suppressor p53. This activation resulted in elevated expression and phosphorylation of heat shock protein beta-1 (HSPB1), a chaperone that defends against protein aggregation. In the amyloidosis-induced mice, the hepatic p38 MAPK-related adaptive responses were additively enhanced by exercise. We observed that with exercise, greatly increased amounts of phosphorylated HSPB1 accumulated at amyloid deposition areas, which we suspect to inhibit amyloid fibril formation. Collectively, our findings conclude exercise-activated, specific chaperone prevention of amyloidosis, and suggest that exercise may amplify intracellular stress-related protective adaptation pathways against age-associated disorders such as amyloidosis.
Project description:Recently, large-scale human genetics studies identified a rare coding variant in the ABI3 gene that is associated with an increased risk of late-onset Alzheimer’s disease (AD). However, pathways by which ABI3 contributes to the pathogenesis of AD are unknown. To address this critical question, we determined whether loss of ABI3 function affects pathological features of AD in the 5XFAD mouse model. We demonstrate that the deletion of Abi3 locus significantly increases amyloid-b (Ab) accumulation and decreases microglia clustering around the plaques. Furthermore, long-term potentiation is impaired in 5XFAD;Abi3 knock-out (“Abi3-/-”) mice. Moreover, we identified dramatic changes in the proportion of microglia subpopulations in Abi3-/- mice using a single-cell RNA sequencing approach. Mechanistic studies demonstrate that Abi3 knockdown in microglia impairs migration and phagocytosis. Taken together, our study provides the first in vivo functional evidence that loss of ABI3 function may increase the risk of developing AD by affecting Ab accumulation and neuroinflammation.
Project description:To detect total RNA in microglia derived from AD mice (5xFAD) brain we single cell sorted Cd11b+ and Cd45+ cells divided by Methoxy-X04 staining (Ab aggregates) positivity We performed differentially expression analysis of RNA-seq of wild-type microglia (Me-X04 neg), non-phagocytic AD microglia (Me-X04 neg), phagocytic AD microglia (Me-X04 positive)
Project description:To detect miRNAs in microglia derived from AD mice (5xFAD) brain we single cell sorted Cd11b+ and Cd45+ cells divided by Methoxy-X04 staining (Ab aggregates) positivity We performed differentially expression analysis of RNA-seq of wild-type microglia (Me-X04 neg), non-phagocytic AD microglia (Me-X04 neg), phagocytic AD microglia (Me-X04 positive)