Severe white matter astrocytopathy in CADASIL

• Published in: Brain pathology (Zurich, Switzerland) Vol. 28; no. 6; pp. 832 - 843
• Main Authors: Hase, Yoshiki, Chen, Aiqing, Bates, Letitia L., Craggs, Lucinda J.L., Yamamoto, Yumi, Gemmell, Elizabeth, Oakley, Arthur E., Korolchuk, Viktor I., Kalaria, Raj N.
• Format: Journal Article
• Language: English
• Published: Switzerland John Wiley & Sons, Inc 01.11.2018; John Wiley and Sons Inc
• Subjects: Adult; Aged; Aged, 80 and over; Aquaporin 4; Aquaporin 4 - metabolism; Astrocytes; Astrocytes - metabolism; Astrocytes - pathology; Autophagy; Autopsy; Brain; C cells; CADASIL; CADASIL - metabolism; CADASIL - pathology; Caspase; Caspase 3 - metabolism; Cell death; Damage assessment; Degeneration; Disease control; Eutrophication; Female; Glial fibrillary acidic protein; Glial Fibrillary Acidic Protein - metabolism; Humans; Immunoreactivity; Leukoencephalopathy; Magnetic resonance imaging; Male; Markers; Microtubule-Associated Proteins - metabolism; Middle Aged; Neurodegeneration; Phagocytosis; Proteins; Sequestosome-1 Protein - metabolism; stroke; Substantia alba; Temporal Lobe - metabolism; vascular dementia; Vascular diseases; white matter; White Matter - pathology; white matter; CADASIL; autophagy; Astrocytes; stroke; vascular dementia
• ISSN: 1015-6305; 1750-3639; 1750-3639
• DOI: 10.1111/bpa.12621

Objectives Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by strategic white matter (WM) hyperintensities on MRI. Pathological features include WM degeneration, arteriolosclerosis, lacunar infarcts, and the deposition of granular osmiophilic material. Based on the hypothesis that the gliovascular unit is compromised, we assessed the nature of astrocyte damage in the deep WM of CADASIL subjects. Methods We evaluated post‐mortem brains from CADASIL, cerebral small vessel disease, similar age cognitively normal and older control subjects. Standard immunohistochemical, immunofluorescent, and unbiased stereological methods were used to evaluate the distribution of astrocytes, microvessels, and autophagy markers in five different brain regions. Results Compared to the controls, the deep WM of CADASIL subjects overall showed increased numbers of glial fibrillary acidic protein (GFAP)‐positive clasmatodendritic astrocytes (P=0.037) and a decrease in the percentage of normal appearing astrocytes (P=0.025). In accord with confluent WM hyperintensities, the anterior temporal pole contained abundant clasmatodendritic astrocytes with displaced aquaporin 4 immunoreactivity. Remarkably, we also found strong evidence for the immunolocalization of autophagy markers including microtubule‐associated protein 1, light chain 3 (LC3), and sequestosome 1/p62 and Caspase‐3 in GFAP‐positive clasmatodendritic cells, particularly within perivascular regions of the deep WM. LC3 was co‐localized in more than 90% of the GFAP‐positive clasmatodendrocytes. Conclusions Our novel findings show astrocytes undergo autophagy‐like cell death in CADASIL, with the anterior temporal pole being highly vulnerable. We propose astrocytes transform from normal appearing type A to hypertrophic type B and eventually to clasmatodendritic type C cells. These observations also suggest the gliovascular unit of the deep WM is severely impaired in CADASIL.