Altered microglia and neurovasculature in the Alzheimer's disease cerebellum.

Traditionally regarded to coordinate movement, the cerebellum also exerts non-motor functions including the regulation of cognitive and behavioral processing, suggesting a potential role in neurodegenerative conditions affecting cognition, such as Alzheimer's disease (AD). This study aims to investigate neuropathology and AD-related molecular changes within the neocerebellum using post-mortem human brain tissue microarrays (TMAs). Immunohistochemistry was conducted on neocerebellar paraffin-embedded TMAs from 24 AD and 24 matched control cases, and free-floating neocerebellar sections from 6 AD and 6 controls. Immunoreactivity was compared between control and AD groups for neuropathological hallmarks (amyloid-β, tau, ubiquitin), Purkinje cells (calbindin), microglia (IBA1, HLA-DR), astrocytes (GFAP) basement-membrane associated molecules (fibronectin, collagen IV), endothelial cells (CD31/PECAM-1) and mural cells (PDGFRβ, αSMA). Amyloid-β expression (total immunolabel intensity) and load (area of immunolabel) was increased by >4-fold within the AD cerebellum. Purkinje cell counts, ubiquitin and tau immunoreactivity were unchanged in AD. IBA1 expression and load was increased by 91% and 69%, respectively, in AD, with no change in IBA1-positive cell number. IBA1-positive cell process length and branching was reduced by 22% and 41%, respectively, in AD. HLA-DR and GFAP immunoreactivity was unchanged in AD. HLA-DR-positive cell process length and branching was reduced by 33% and 49%, respectively, in AD. Fibronectin expression was increased by 27% in AD. Collagen IV, PDGFRβ and αSMA immunoreactivity was unchanged in AD. The number of CD31-positive vessels was increased by 98% in AD, suggesting the increase in CD31 expression and load in AD is due to greater vessel number. The PDGFRβ/CD31 load ratio was reduced by 59% in AD. These findings provide evidence of molecular changes affecting microglia and the neurovasculature within the AD neocerebellum. These changes, occurring without overt neuropathology, support the hypothesis of microglial and neurovascular dysfunction as drivers of AD, which has implications on the neocerebellar contribution to AD symptomatology and pathophysiology.