Astrocytic Hevin/SPARCL-1 regulates cognitive decline in pathological and normal brain aging

Introduction: Dementia presents a global health challenge. Here, we aim to evaluate the involvement of astrocytes, primary glial cells in the brain, in ameliorating cognitive deterioration. We have explored the influence of Hevin (SPARCL-1), a secreted glycoprotein from the secreted protein acidic and rich in cysteine (SPARC) family, on cognitive decline in both normal and pathological brain aging. Prior research has associated Sparcl1 mutations with accelerated onset of Alzheimer's disease (AD), suggesting Hevin's role in age-related cognitive decline.

Methods: Using adeno-associated viruses (AAV), we enhanced Hevin expression in hippocampal astrocytes of middle-aged APP/PSEN transgenic mice, an established AD model, and middle-aged wild-type animals. Next, we conducted various cognitive assessments followed by proteomic analysis, quantification of Ab plaques, and assessment of pre- and postsynaptic marker co-localization.

Results: Our results show that astrocytic Hevin overexpression mitigates cognitive decline, as indicated by behavioral tests, increased co-localization of pre- and post-synaptic markers, and altered expression of synaptic mediators revealed through proteomic analysis. Hevin overexpression in astrocytes did not affect Aβ plaque deposition in the hippocampus, a hallmark of AD pathology. Moreover, middle-aged wild-type animals also exhibited enhanced cognitive performance following astrocytic Hevin overexpression.

Conclusion: Our findings suggest that astrocytic Hevin delays cognitive impairment in both normal and pathological brain aging by modulating hippocampal synapse composition independent of Aβ plaque accumulation. This study identifies astrocytic Hevin as a potential therapeutic target for age-related cognitive decline, offering valuable insights for the development of glial-based interventions in AD and cognitive decline overall.

Support: CNPq,FAPERJ,FAPESP, Ministério da Saúde,Instituto Nacional de Neurociência Translacional