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 inner...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2019-07-01
|
| Series: | Frontiers in Aging Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fnagi.2019.00172/full |
| _version_ | 1818297538145419264 |
|---|---|
| author | Shereen Nizari Roxana O. Carare Ignacio A. Romero Cheryl A. Hawkes |
| author_facet | Shereen Nizari Roxana O. Carare Ignacio A. Romero Cheryl A. Hawkes |
| author_sort | Shereen Nizari |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T04:21:01Z |
| format | Article |
| id | doaj.art-e0126da7cfbc4bdf9d53e22d958468db |
| institution | Directory Open Access Journal |
| issn | 1663-4365 |
| language | English |
| last_indexed | 2024-12-13T04:21:01Z |
| publishDate | 2019-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj.art-e0126da7cfbc4bdf9d53e22d958468db2022-12-21T23:59:47ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652019-07-011110.3389/fnagi.2019.001724603383D Reconstruction of the Neurovascular Unit Reveals Differential Loss of Cholinergic Innervation in the Cortex and Hippocampus of the Adult Mouse BrainShereen Nizari0Roxana O. Carare1Ignacio A. Romero2Cheryl A. Hawkes3School of Life, Health and Chemical Science, Faculty of Science, Technology, Engineering and Mathematics, The Open University, Milton Keynes, United KingdomClinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United KingdomSchool of Life, Health and Chemical Science, Faculty of Science, Technology, Engineering and Mathematics, The Open University, Milton Keynes, United KingdomSchool of Life, Health and Chemical Science, Faculty of Science, Technology, Engineering and Mathematics, The Open University, Milton Keynes, United KingdomIncreasing 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.https://www.frontiersin.org/article/10.3389/fnagi.2019.00172/fullneurovascular unitcholinergicAlzheimer’s diseasecerebral amyloid angiopathycortexhippocampus |
| spellingShingle | Shereen Nizari Roxana O. Carare Ignacio A. Romero Cheryl A. Hawkes 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 neurovascular unit cholinergic Alzheimer’s disease cerebral amyloid angiopathy cortex hippocampus |
| title | 3D Reconstruction of the Neurovascular Unit Reveals Differential Loss of Cholinergic Innervation in the Cortex and Hippocampus of the Adult Mouse Brain |
| title_full | 3D Reconstruction of the Neurovascular Unit Reveals Differential Loss of Cholinergic Innervation in the Cortex and Hippocampus of the Adult Mouse Brain |
| title_fullStr | 3D Reconstruction of the Neurovascular Unit Reveals Differential Loss of Cholinergic Innervation in the Cortex and Hippocampus of the Adult Mouse Brain |
| title_full_unstemmed | 3D Reconstruction of the Neurovascular Unit Reveals Differential Loss of Cholinergic Innervation in the Cortex and Hippocampus of the Adult Mouse Brain |
| title_short | 3D Reconstruction of the Neurovascular Unit Reveals Differential Loss of Cholinergic Innervation in the Cortex and Hippocampus of the Adult Mouse Brain |
| title_sort | 3d reconstruction of the neurovascular unit reveals differential loss of cholinergic innervation in the cortex and hippocampus of the adult mouse brain |
| topic | neurovascular unit cholinergic Alzheimer’s disease cerebral amyloid angiopathy cortex hippocampus |
| url | https://www.frontiersin.org/article/10.3389/fnagi.2019.00172/full |
| work_keys_str_mv | AT shereennizari 3dreconstructionoftheneurovascularunitrevealsdifferentiallossofcholinergicinnervationinthecortexandhippocampusoftheadultmousebrain AT roxanaocarare 3dreconstructionoftheneurovascularunitrevealsdifferentiallossofcholinergicinnervationinthecortexandhippocampusoftheadultmousebrain AT ignacioaromero 3dreconstructionoftheneurovascularunitrevealsdifferentiallossofcholinergicinnervationinthecortexandhippocampusoftheadultmousebrain AT cherylahawkes 3dreconstructionoftheneurovascularunitrevealsdifferentiallossofcholinergicinnervationinthecortexandhippocampusoftheadultmousebrain |