The characteristics of perivascular proinflammation in 4‐repeat tauopathies

Abstract

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are both neurodegenerative diseases characterized by aggregates composed of 4‐repeat (4R) tau protein. They have distinct neuropathological features and classic clinical symptoms; however, the signs and symptoms overlap across the two syndromes. Accumulating evidence suggests that dysregulated immune response is a major contributing factor to neurodegeneration but its role in 4R‐tauopathies remains undetermined. The aim is to explore the involvement of neuroinflammation from a vascular perspective in 4R‐tauopathies. Autopsies from four controls, three PSP, and three CBD cases were assessed. Samples were obtained from the superior/middle frontal gyrus (S/M‐FG) and basal ganglia (BG). Immunofluorescence staining included neuroinflammatory markers: glial fibrillary acidic protein (GFAP), ionized calcium‐binding adapter molecule 1 (Iba1), cluster of differentiation 68 (CD68); vascular markers: collagen type IV (ColIV), monocarboxylate transporter‐1 (MCT1), and α‐smooth muscle actin ( α SMA). Maximally projected confocal z‐stack images of vasculature were used as a mask to quantify total perivascular GFAP+/Iba1+/CD68+ labeling. GFAP immunoreactivity ratio between MCT1 and α SMA double labeled arteries and veins was quantified to further differentiate venular and arteriolar involvement into proinflammatory activation. Both PSP and CBD had widespread perivascular proinflammatory changes, although greater in CBD. The activated GFAP+ astrocytes and microglia/macrophages in CBD were distributed extensively in S/M‐FG and BG, with S/M‐FG WM more affected. In PSP, abundant neuroinflammation was found in BG. The involvement of vasculature type was distinct among the two 4R‐tauopathies, while CBD showed comparable proinflammatory changes in arterioles and venules, PSP exhibited predominant proinflammation in venules. The regional pattern of perivascular proinflammation differed between PSP and CBD, corresponding to the characteristic affected brain regions. CBD had more severe perivascular proinflammation that involved both arterioles and venules, while venules were more affected in PSP. Perivascular proinflammation may be a critical pathophysiological process in 4R‐tauopathies.