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3D reconstruction of the neurovascular unit reveals differential loss of cholinergic innervation in the cortex and hippocampus of the adult mouse brain

3D reconstruction of the neurovascular unit reveals differential loss of cholinergic innervation in the cortex and hippocampus of the adult mouse brain
3D reconstruction of the neurovascular unit reveals differential loss of cholinergic innervation in the cortex and hippocampus of the adult mouse brain

Increasing evidence supports a role for cerebrovasculature dysfunction in the etiology of Alzheimer's disease (AD). Blood vessels in the brain are composed of a collection of cells and acellular material that comprise the neurovascular unit (NVU). The NVU in the hippocampus and cortex receives innervation from cholinergic neurons that originate in the basal forebrain. Death of these neurons and their nerve fibers is an early feature of AD. However, the effect of the loss of cholinergic innervation on the NVU is not well characterized. The purpose of this study was to evaluate the effect of the loss of cholinergic innervation of components of the NVU at capillaries, arteries and veins in the hippocampus and cortex. Adult male C57BL/6 mice received an intracerebroventricular injection of the immunotoxin p75NTR mu-saporin to induce the loss of cholinergic neurons. Quadruple labeling immunohistochemistry and 3D reconstruction were carried out to characterize specific points of contact between cholinergic fibers and collagen IV, smooth muscle cells and astrocyte endfeet. Innate differences were observed between vessels of the hippocampus and cortex of control mice, including a greater amount of cholinergic contact with perivascular astrocytes in hippocampal capillaries and a thicker basement membrane in hippocampal veins. Saporin treatment induced a loss of cholinergic innervation at the arterial basement membrane and smooth muscle cells of both the hippocampus and the cortex. In the cortex, there was an additional loss of innervation at the astrocytic endfeet. The current results suggest that cortical arteries are more strongly affected by cholinergic denervation than arteries in the hippocampus. This regional variation may have implications for the etiology of the vascular pathology that develops in AD.

Alzheimer's disease, Cerebral amyloid angiopathy, Cholinergic, Cortex, Hippocampus, Neurovascular unit
1663-4365
1-15
Nizari, Shereen
2fd944bb-e54c-4520-9119-fef89e873b1f
Carare, Roxana O.
0478c197-b0c1-4206-acae-54e88c8f21fa
Romero, Ignacio A.
2f34d234-c19e-41f1-9062-064c7830a8f3
Hawkes, Cheryl A.
031a17ac-0931-4ff9-93cc-df8cb58e14f7
Nizari, Shereen
2fd944bb-e54c-4520-9119-fef89e873b1f
Carare, Roxana O.
0478c197-b0c1-4206-acae-54e88c8f21fa
Romero, Ignacio A.
2f34d234-c19e-41f1-9062-064c7830a8f3
Hawkes, Cheryl A.
031a17ac-0931-4ff9-93cc-df8cb58e14f7

Nizari, Shereen, Carare, Roxana O., Romero, Ignacio A. and Hawkes, Cheryl A. (2019) 3D reconstruction of the neurovascular unit reveals differential loss of cholinergic innervation in the cortex and hippocampus of the adult mouse brain. Frontiers in Aging Neuroscience, 10 (JUL), 1-15. (doi:10.3389/fnagi.2019.00172).

Record type: Article

Abstract

Increasing evidence supports a role for cerebrovasculature dysfunction in the etiology of Alzheimer's disease (AD). Blood vessels in the brain are composed of a collection of cells and acellular material that comprise the neurovascular unit (NVU). The NVU in the hippocampus and cortex receives innervation from cholinergic neurons that originate in the basal forebrain. Death of these neurons and their nerve fibers is an early feature of AD. However, the effect of the loss of cholinergic innervation on the NVU is not well characterized. The purpose of this study was to evaluate the effect of the loss of cholinergic innervation of components of the NVU at capillaries, arteries and veins in the hippocampus and cortex. Adult male C57BL/6 mice received an intracerebroventricular injection of the immunotoxin p75NTR mu-saporin to induce the loss of cholinergic neurons. Quadruple labeling immunohistochemistry and 3D reconstruction were carried out to characterize specific points of contact between cholinergic fibers and collagen IV, smooth muscle cells and astrocyte endfeet. Innate differences were observed between vessels of the hippocampus and cortex of control mice, including a greater amount of cholinergic contact with perivascular astrocytes in hippocampal capillaries and a thicker basement membrane in hippocampal veins. Saporin treatment induced a loss of cholinergic innervation at the arterial basement membrane and smooth muscle cells of both the hippocampus and the cortex. In the cortex, there was an additional loss of innervation at the astrocytic endfeet. The current results suggest that cortical arteries are more strongly affected by cholinergic denervation than arteries in the hippocampus. This regional variation may have implications for the etiology of the vascular pathology that develops in AD.

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Accepted/In Press date: 20 June 2019
e-pub ahead of print date: 4 July 2019
Keywords: Alzheimer's disease, Cerebral amyloid angiopathy, Cholinergic, Cortex, Hippocampus, Neurovascular unit

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Local EPrints ID: 433580
URI: https://eprints.soton.ac.uk/id/eprint/433580
ISSN: 1663-4365
PURE UUID: b491e9bd-5710-4d20-a9d1-811cbe13f1e8

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Date deposited: 28 Aug 2019 16:30
Last modified: 09 Sep 2019 16:30

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