Basic Science and Pathogenesis.

Background: Tauopathies are a group of neurodegenerative disorders which are characterized by the accumulation of abnormal tau protein in the brain. However, the mechanistic understanding of pathogenic tau formation and spread within the brain remains elusive. Astrocytes are major immune reactive cells in the brain and have been implicated in exacerbating tau pathology by releasing extracellular vesicles (AEVs) containing pro-inflammatory cytokines and chemokines upon activation.

Basic Science and Pathogenesis.

Background: We previously identified the novel mechanism of pathological tau transfer via extracellular vesicles (EVs) in Alzheimer's disease (AD). Targeting EV secretion to mitigate tau transfer is therefore a promising therapeutic approach for AD. P2X purinoreceptor 7 (P2RX7), an ATP-gated cationic channel, regulates microvesicle shedding or secretion of multivesicular body-derived exosomes.

Basic Science and Pathogenesis.

Background: Extracellular vesicles (EVs) carry pathogenic molecules and play a role in the disease spread, including aggregated tau proteins. The Endosomal Sorting Complexes Required for Transport (ESCRT) machinery is responsible for the biogenesis of small EVs (exosomes), thus targeting critical ESCRT molecules can disrupt EV synthesis. We hypothesize that microglia-specific targeting of ESCRT-I molecule Tsg101 suppresses microglia-derived EV-mediated propagation of tau pathology, leading to amelioration of the disease phenotype of the tauopathy mouse model.

Basic Science and Pathogenesis.

Background: The efficacy of Calorie Restriction (CR) in enhancing cognition, promoting healthy aging, and extending lifespan is well-established. Yet, it remains unclear whether the apolipoprotein E (APOE) genotype, a known modifier for aging and age-related disorders, influences the beneficial effects of CR in countering aging.

Methods: To investigate this question, we utilized humanized APOE mouse models, which express APOE2, APOE3, or APOE4 alleles systematically (refer to as E2, E3, and E4 mice).

Selenoprotein P is a target for regulating extracellular vesicle biogenesis and secretion from activated microglia in vivo.

Microglia, brain innate immune cells, participate in the spread of inflammatory signals and aggregated proteins through secretion of extracellular vesicles (EVs). Selenoprotein P (Sepp1) is a potential regulator of microglial EV secretion. Here, we investigate the effect of Sepp1 silencing on microglial transcriptomics to elucidate the Sepp1 regulatory mechanism of EV secretion and validate this effect in APP knockin mice.