Hase, Y, Chen, A, Bates, LL et al. (6 more authors) (2018) Severe White Matter Astrocytopathy in CADASIL. Brain pathology (Zurich, Switzerland), 28 (6). pp. 832-843. ISSN 1015-6305
Abstract
Objectives
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterised 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 immunolocalisation 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‐localised 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | (c) 2018 International Society of Neuropathology. This is the pre-peer reviewed version of the following article: Hase, Y, Chen, A, Bates, LL et al. (6 more authors) (2018) Severe White Matter Astrocytopathy in CADASIL. Brain pathology, which has been published in final form at https://doi.org/10.1111/bpa.12621. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. |
Keywords: | Astrocytes; autophagy; CADASIL; stroke; vascular dementia; white matter |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Discovery & Translational Science Dept (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 22 May 2018 10:21 |
Last Modified: | 14 May 2019 00:39 |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1111/bpa.12621 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:131114 |