Investigating Neurovascular Unit Aging in a Mouse Model of Autism

Abstract

Ageing is the primary risk factor for most neurodegenerative diseases. While neurodevelopmental disorders, neuropsychiatric conditions, and neurodegenerative diseases are clinically expressed at different points during the lifespan and present distinct clinical features, these conditions share common cerebrovascular abnormalities. Growing evidence link cerebrovascular dysfunction to neurodegeneration, yet the early origins of these vascular impairments remain unclear. Identifying early changes is crucial for designing effective and/or preventive therapeutic strategies.

This thesis aims to investigate neurovascular unit (NVU) ageing in a 16p.11.2 deletion (16p.11.2ᵈᶠᐟ⁺) mouse model of autism spectrum disorder (ASD). While we previously demonstrated that 16p.11.2ᵈᶠᐟ⁺ mice exhibit early-life NVU alterations, whether these initial deficits alter NVU ageing trajectory remains unknown. To answer these questions, we used multiple approaches to assess morphological and molecular NVU ageing. Using transmission electron microscopy to assess NVU characteristics in the cerebral cortex, we found that aged 16p.11.2ᵈᶠᐟ⁺ mice exhibit a pronounced, age-related decrease in the number of astroglia endfeet, a premature endfoot hypertrophy, and basement membrane thickening. Furthermore, immunohistochemistry for Glial Fibrillary Acidic Protein showed increased levels of reactive astrocytes in the stratum radiatum and stratum lacunosum-moleculare layers of the hippocampus CA1 region in middle-aged 16p.11.2ᵈᶠᐟ⁺ mice. Moreover, Aquaporin-4, a marker for water channel present in astroglial endfeet, displayed a premature decrease on vessels from aged 16p.11.2ᵈᶠᐟ⁺ mice. Collectively, our findings suggest a modified trajectory of ageing in this ASD mouse model and provide novel insights on NVU structural and morphological decline.