Distinct changes in all major components of the neurovascular unit across different neuropathological stages of Alzheimer's disease

Sep 1, 2020Brain pathology (Zurich, Switzerland)

Clear changes in all main parts of the brain's blood vessel system at different stages of Alzheimer's disease

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Abstract

Altered vascular distribution in Alzheimer's disease (AD) patients showed a reduced nearest distance between capillaries.

A Braak-stage dependent reduction in pericyte coverage was identified as the earliest structural alteration during AD progression.
Astrocyte coverage within the neurovascular unit (NVU) was significantly higher in AD patients compared to non-demented elderly controls.
Microglial coverage around capillaries was reduced in AD patients.
Perivascular macrophages were relocated from leptomeningeal arteries to penetrating parenchymal vessels in AD patients.
All components of the NVU exhibited distinct alterations during the progression of AD.

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In the brain capillaries, endothelial cells, pericytes, astrocytes and microglia form a structural and functional complex called neurovascular unit (NVU) which is critically involved in maintaining neuronal homeostasis. In the present study, we applied a comprehensive immunohistochemical approach to investigate the structural alterations in the NVU across different Alzheimer's disease (AD) neuropathological stages. Post-mortem human cortical and hippocampal samples derived from AD patients and non-demented elderly control individuals were immunostained using a panel of markers representing specific components of the NVU including Collagen IV (basement membrane), PDGFR-β (pericytes), GFAP (astrocytes), Iba1 (microglia), MRC1 (perivascular macrophages) and lectin as an endothelial cell label. Astrocytes (GFAP) and microglia (Iba1) were quantified both in the whole visual-field and specifically within the NVU, and the sample set was additionally analyzed using anti-tau (AT8) and three different anti-Aβ (clones G2-10, G2-11, 4G8) antibodies. Analyses of lectin labeled sections showed an altered vascular distribution in AD patients as revealed by a reduced nearest distance between capillaries. Within the NVU, a Braak-stage dependent reduction in pericyte coverage was identified as the earliest structural alteration during AD progression. In comparison to non-demented elderly controls, AD patients showed a significantly higher astrocyte coverage within the NVU, which was paralleled by a reduced microglial coverage around capillaries. Assessment of perivascular macrophages moreover demonstrated a relocation of these cells from leptomeningeal arteries to penetrating parenchymal vessels in AD patients. Collectively, the results of our study represent a comprehensive first in-depth analysis of AD-related structural changes in the NVU and suggest distinct alterations in all components of the NVU during AD progression.

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Distinct changes in all major components of the neurovascular unit across different neuropathological stages of Alzheimer's disease

Abstract

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