Project description:APOE, a well-established genetic risk factor for Alzheimer’s disease, is also closely associated with the aging process. Previous studies have demonstrated age-related declines in APOE expression within astrocytes. To investigate the mechanisms underlying this reduction, in this study, we performed small RNA sequencing on extracellular vesicles (EVs) derived from human fetal brain astrocytes. Our findings reveal miR-let-7b, enriched in astrocyte-derived EVs, as a key mediator of age-related APOE downregulation. Furthermore, we uncover a novel role for APOE in regulating astrocyte senescence, providing new insights into the molecular interplay between aging and neurodegenerative disorders.
Project description:The excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter in the brain expressed predominantly in astrocytes and at low levels in neurons and axonal terminals. EAAT2 expression is reduced in aging and sporadic Alzheimer’s disease (AD) patients’ brains. The role EAAT2 plays in cognitive aging and its associated mechanisms remains largely unknown. Here, we show that conditional deletion of astrocytic and neuronal EAAT2 results in age-related cognitive deficits. Astrocytic, but not neuronal EAAT2, deletion leads to early deficits in short-term memory and in spatial reference learning and long-term memory. Neuronal EAAT2 loss results in late-onset spatial reference long-term memory deficit. Neuronal EAAT2 deletion leads to dysregulation of the kynurenine pathway, and astrocytic EAAT2 deficiency results in dysfunction of innate and adaptive immune pathways, which correlate with cognitive decline. Astrocytic EAAT2 deficiency also shows transcriptomic overlaps with human aging and AD. Overall, the present study shows that in addition to the widely recognized astrocytic EAAT2, neuronal EAAT2 plays a role in hippocampus-dependent memory. Furthermore, the gene expression profiles associated with astrocytic and neuronal EAAT2 deletion are substantially different, with the former associated with inflammation and synaptic function similar to changes observed in human AD and gene expression changes associated with inflammation similar to the aging human brain.
Project description:The e4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer's disease and has been shown to increase amyloid pathology relative to the presence of the e2 and e3 alleles. In the brain, apoE is primarily produced by astrocytes and under pathological conditions also by microglia. The cell-type-specific role of apoE in amyloid pathology, especially after amyloid plaque deposition, has not been fully elucidated. We generated APPPS1-21/Aldh1l1-Cre/ERT2/apoE4flox/flox and APPPS1-21/apoE4flox/flox mice. At 3.8-months-of-age, during the phase of rapid plaque growth, we administered tamoxifen to reduce astrocytic APOE4 and assessed mice at 6-months-of-age. One day before tamoxifen treatment, mice were injected with methoxy-X04, a blood-brain-barrier permeant fluorescent marker that labeled the pre-existing fibrillar amyloid plaques. By using this strategy, we were able to characterize pre-existing plaques prior to the loss of astrocytic APOE4 and to also analyze newly-formed amyloid plaques after the loss of astrocytic APOE4. Interestingly, astrocytic APOE4 deletion strongly reduced pre-existing plaques. It also prevented new plaque formation and decreased glial reactivity. Importantly, the removal of astrocytic APOE4 resulted in enhanced microglial and astrocytic phagocytic ability, which may contribute to the reduction of the amyloid pathology.
Project description:Despite the dramatic changes in morphology occurring in the seminal vesicles during aging, the transcriptomic characteristics are poorly understood. Thus, we performed a bulk RNA sequencing on seminal vesicle samples from 3-month-old, 13-month-old, and 21-month-old mice to elucidate transcriptomic changes in this study. Comparing 3-month-old mice with the 21-month-old, inflammatory and immune response were identified as the most significantly biological process in upregulated differentially expressed genes (DEGs). Meanwhile, “chemokine signaling pathway” was identified as a key pathway. Indeed, a series of DEGs were enriched in “chemokine signaling pathway”, including Ccl6, Ccl8, Ccl9, Ccr2, Ccr5 and Ccr7. Hub genes such as Ptprc, Adgre1, H2-Ab1 and Ctss were obtained through Protein-Protein interaction network analysis among the continuously up-regulated differentially expressed genes in mouse seminal vesicles at three different ages. These analyses revealed an increased status of immune and inflammatory response in the aged seminal vesicles. In addition, multiple aging-associated DEGs were identified, including Vcam1, Apoe and Cdkn1a. To our knowledge, this study is the first to investigate the general transcriptome landscape of the seminal vesicles in a murine model of natural aging, which may provide novel insights involved in aging-related seminal vesicle dysfunction.