ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice
Abstract Background Alzheimer’s disease (AD) is defined by amyloid beta (Aβ) plaques and neurofibrillary tangles and characterized by neurodegeneration and memory loss. The majority of AD patients also have Aβ deposition in cerebral vessels known as cerebral amyloid angiopathy (CAA), microhemorrhage...
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| Format: | Article |
| Language: | English |
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BMC
2019-05-01
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| Series: | Alzheimer’s Research & Therapy |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13195-019-0497-9 |
| _version_ | 1819077757350445056 |
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| author | Emily B. Button Guilaine K. Boyce Anna Wilkinson Sophie Stukas Arooj Hayat Jianjia Fan Brennan J. Wadsworth Jerome Robert Kris M. Martens Cheryl L. Wellington |
| author_facet | Emily B. Button Guilaine K. Boyce Anna Wilkinson Sophie Stukas Arooj Hayat Jianjia Fan Brennan J. Wadsworth Jerome Robert Kris M. Martens Cheryl L. Wellington |
| author_sort | Emily B. Button |
| collection | DOAJ |
| description | Abstract Background Alzheimer’s disease (AD) is defined by amyloid beta (Aβ) plaques and neurofibrillary tangles and characterized by neurodegeneration and memory loss. The majority of AD patients also have Aβ deposition in cerebral vessels known as cerebral amyloid angiopathy (CAA), microhemorrhages, and vascular co-morbidities, suggesting that cerebrovascular dysfunction contributes to AD etiology. Promoting cerebrovascular resilience may therefore be a promising therapeutic or preventative strategy for AD. Plasma high-density lipoproteins (HDL) have several vasoprotective functions and are associated with reduced AD risk in some epidemiological studies and with reduced Aβ deposition and Aβ-induced inflammation in 3D engineered human cerebral vessels. In mice, deficiency of apoA-I, the primary protein component of HDL, increases CAA and cognitive dysfunction, whereas overexpression of apoA-I from its native promoter in liver and intestine has the opposite effect and lessens neuroinflammation. Similarly, acute peripheral administration of HDL reduces soluble Aβ pools in the brain and some studies have observed reduced CAA as well. Here, we expand upon the known effects of plasma HDL in mouse models and in vitro 3D artery models to investigate the interaction of amyloid, astrocytes, and HDL on the cerebrovasculature in APP/PS1 mice. Methods APP/PS1 mice deficient or hemizygous for Apoa1 were aged to 12 months. Plasma lipids, amyloid plaque deposition, Aβ protein levels, protein and mRNA markers of neuroinflammation, and astrogliosis were assessed using ELISA, qRT-PCR, and immunofluorescence. Contextual and cued fear conditioning were used to assess behavior. Results In APP/PS1 mice, complete apoA-I deficiency increased total and vascular Aβ deposition in the cortex but not the hippocampus compared to APP/PS1 littermate controls hemizygous for apoA-I. Markers of both general and vascular neuroinflammation, including Il1b mRNA, ICAM-1 protein, PDGFRβ protein, and GFAP protein, were elevated in apoA-I-deficient APP/PS1 mice. Additionally, apoA-I-deficient APP/PS1 mice had elevated levels of vascular-associated ICAM-1 in the cortex and hippocampus and vascular-associated GFAP in the cortex. A striking observation was that astrocytes associated with cerebral vessels laden with Aβ or associated with Aβ plaques showed increased reactivity in APP/PS1 mice lacking apoA-I. No behavioral changes were observed. Conclusions ApoA-I-containing HDL can reduce amyloid pathology and astrocyte reactivity to parenchymal and vascular amyloid in APP/PS1 mice. |
| first_indexed | 2024-12-21T19:02:16Z |
| format | Article |
| id | doaj.art-fb2a691f58d94abb8998aa69e3f67f4a |
| institution | Directory Open Access Journal |
| issn | 1758-9193 |
| language | English |
| last_indexed | 2024-12-21T19:02:16Z |
| publishDate | 2019-05-01 |
| publisher | BMC |
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| series | Alzheimer’s Research & Therapy |
| spelling | doaj.art-fb2a691f58d94abb8998aa69e3f67f4a2022-12-21T18:53:27ZengBMCAlzheimer’s Research & Therapy1758-91932019-05-0111111810.1186/s13195-019-0497-9ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 miceEmily B. Button0Guilaine K. Boyce1Anna Wilkinson2Sophie Stukas3Arooj Hayat4Jianjia Fan5Brennan J. Wadsworth6Jerome Robert7Kris M. Martens8Cheryl L. Wellington9Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British ColumbiaDepartment of Surgery, Providence Health Care Research InstituteDepartment of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British ColumbiaDepartment of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British ColumbiaDepartment of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British ColumbiaDepartment of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British ColumbiaPathology and Laboratory Medicine, Faculty of Medicine, University of British ColumbiaDepartment of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British ColumbiaDepartment of Psychology, West Virginia UniversityDepartment of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British ColumbiaAbstract Background Alzheimer’s disease (AD) is defined by amyloid beta (Aβ) plaques and neurofibrillary tangles and characterized by neurodegeneration and memory loss. The majority of AD patients also have Aβ deposition in cerebral vessels known as cerebral amyloid angiopathy (CAA), microhemorrhages, and vascular co-morbidities, suggesting that cerebrovascular dysfunction contributes to AD etiology. Promoting cerebrovascular resilience may therefore be a promising therapeutic or preventative strategy for AD. Plasma high-density lipoproteins (HDL) have several vasoprotective functions and are associated with reduced AD risk in some epidemiological studies and with reduced Aβ deposition and Aβ-induced inflammation in 3D engineered human cerebral vessels. In mice, deficiency of apoA-I, the primary protein component of HDL, increases CAA and cognitive dysfunction, whereas overexpression of apoA-I from its native promoter in liver and intestine has the opposite effect and lessens neuroinflammation. Similarly, acute peripheral administration of HDL reduces soluble Aβ pools in the brain and some studies have observed reduced CAA as well. Here, we expand upon the known effects of plasma HDL in mouse models and in vitro 3D artery models to investigate the interaction of amyloid, astrocytes, and HDL on the cerebrovasculature in APP/PS1 mice. Methods APP/PS1 mice deficient or hemizygous for Apoa1 were aged to 12 months. Plasma lipids, amyloid plaque deposition, Aβ protein levels, protein and mRNA markers of neuroinflammation, and astrogliosis were assessed using ELISA, qRT-PCR, and immunofluorescence. Contextual and cued fear conditioning were used to assess behavior. Results In APP/PS1 mice, complete apoA-I deficiency increased total and vascular Aβ deposition in the cortex but not the hippocampus compared to APP/PS1 littermate controls hemizygous for apoA-I. Markers of both general and vascular neuroinflammation, including Il1b mRNA, ICAM-1 protein, PDGFRβ protein, and GFAP protein, were elevated in apoA-I-deficient APP/PS1 mice. Additionally, apoA-I-deficient APP/PS1 mice had elevated levels of vascular-associated ICAM-1 in the cortex and hippocampus and vascular-associated GFAP in the cortex. A striking observation was that astrocytes associated with cerebral vessels laden with Aβ or associated with Aβ plaques showed increased reactivity in APP/PS1 mice lacking apoA-I. No behavioral changes were observed. Conclusions ApoA-I-containing HDL can reduce amyloid pathology and astrocyte reactivity to parenchymal and vascular amyloid in APP/PS1 mice.http://link.springer.com/article/10.1186/s13195-019-0497-9Alzheimer’s diseaseHigh-density lipoproteinsApolipoprotein A-I (apoA-I)Amyloid betaCerebral amyloid angiopathyNeuroinflammation |
| spellingShingle | Emily B. Button Guilaine K. Boyce Anna Wilkinson Sophie Stukas Arooj Hayat Jianjia Fan Brennan J. Wadsworth Jerome Robert Kris M. Martens Cheryl L. Wellington ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice Alzheimer’s Research & Therapy Alzheimer’s disease High-density lipoproteins Apolipoprotein A-I (apoA-I) Amyloid beta Cerebral amyloid angiopathy Neuroinflammation |
| title | ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice |
| title_full | ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice |
| title_fullStr | ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice |
| title_full_unstemmed | ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice |
| title_short | ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice |
| title_sort | apoa i deficiency increases cortical amyloid deposition cerebral amyloid angiopathy cortical and hippocampal astrogliosis and amyloid associated astrocyte reactivity in app ps1 mice |
| topic | Alzheimer’s disease High-density lipoproteins Apolipoprotein A-I (apoA-I) Amyloid beta Cerebral amyloid angiopathy Neuroinflammation |
| url | http://link.springer.com/article/10.1186/s13195-019-0497-9 |
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