Derevyanko, A. | bioRxiv Science

bioRxiv2024

Astrocyte transcriptomic analysis identifies glypican 5 downregulation as a contributor to synaptic dysfunction in Alzheimer disease models

Synaptic dysfunction is an early feature in Alzheimers disease (AD) and correlates with cognitive decline. Astrocytes are essential regulators of synapses, impacting synapse formation, maturation, elimination and function. To understand if synapse-supportive functions of astrocytes are altered in AD, we used astrocyte BacTRAP mice to generate a comprehensive dataset of hippocampal astrocyte transcriptional alterations in two mouse models of Alzheimers pathology (APPswe/PS1dE9 and Tau P301S), characterizing sex and age-dependent changes. We found that astrocytes from both models downregulate genes important for synapse regulation and function such as the synapse-maturation factor Glypican 5. This transcriptional signature is shared with human post-mortem AD patients. Manipulating a key component of this signature by in vivo overexpression of Glypican 5 in astrocytes is sufficient to prevent early synaptic dysfunction and improve spatial learning in APPswe/PS1dE9 mice. These findings open new avenues to target astrocytic factors to mitigate AD synaptic dysfunction.

neuroscience↗

bioRxiv2021

Small extracellular vesicles from young mice prevent frailty and improve healthspan in old mice.

Aging is associated with an increased risk of frailty, disability, comorbidities, institutionalization, falls, fractures, hospitalization, and mortality. Searching for strategies to delay the degenerative changes associated with aging and frailty is interesting. We treated old animals intravenously with small extracellular vesicles (sEVs) derived from adipose mesenchymal stem cells (ADSCs) of young animals, and we found an improvement of several functional parameters usually altered with aging, such as motor coordination, grip strength, fatigue resistance, fur regeneration, and renal function. Frailty index analysis showed that 40% of old control mice were frail, whereas none of the old ADSCs-sEVs treated mice were. Molecular and structural benefits in muscle and kidney accompanied this functional improvement. ADSCs-sEVs induced pro-regenerative effects and a decrease in oxidative stress, inflammation, and senescence markers. Moreover, predicted epigenetic age was lower in tissues of old mice treated with ADSCs-sEVs and their metabolome changed to a youth-like pattern. Finally, we gained some insight into the miRNAs contained in sEVs that might be, at least in part, responsible for the effects observed. We propose that young sEVs treatment can be beneficial against frailty and therefore can promote healthy aging.

physiology↗