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Heparanase overexpr...
Heparanase overexpression impedes perivascular clearance of amyloid-beta from murine brain : relevance to Alzheimer's disease
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- Zhang, Xiao (author)
- Uppsala universitet,Larhammar: Farmakologi
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- O'Callaghan, Paul (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Li, Honglian (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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- Tan, Ying-Xia (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab,Acad Mil Med Sci, Stem Cell & Regenerat Med Lab, Inst Hlth Serv & Transfus Med, Beijing, Peoples R China.
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- Zhang, Ganlin (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab,Capital Med Univ, Beijing Hosp Tradit Chinese Med, 23,Back Rd Art Gallery, Beijing 100010, Peoples R China.
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- Barash, Uri (author)
- Technion, Canc & Vasc Biol Res Ctr, Rappaport Fac Med, IL-31096 Haifa, Israel.
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- Wang, Xiaomin (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab,Capital Med Univ, Beijing Hosp Tradit Chinese Med, 23,Back Rd Art Gallery, Beijing 100010, Peoples R China.
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- Lannfelt, Lars (author)
- Uppsala universitet,Geriatrik
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- Vlodavsky, Israel (author)
- Technion, Canc & Vasc Biol Res Ctr, Rappaport Fac Med, IL-31096 Haifa, Israel.
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- Lindahl, Ulf (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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- Li, Jin-Ping (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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(creator_code:org_t)
- 2021-05-10
- 2021
- English.
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In: Acta neuropathologica communications. - : BioMed Central (BMC). - 2051-5960. ; 9
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Abstract
Subject headings
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- Defective amyloid-beta (A beta) clearance from the brain is a major contributing factor to the pathophysiology of Alzheimer's disease (AD). A beta clearance is mediated by macrophages, enzymatic degradation, perivascular drainage along the vascular basement membrane (VBM) and transcytosis across the blood-brain barrier (BBB). AD pathology is typically associated with cerebral amyloid angiopathy due to perivascular accumulation of A beta. Heparan sulfate (HS) is an important component of the VBM, thought to fulfill multiple roles in AD pathology. We previously showed that macrophage-mediated clearance of intracortically injected A beta was impaired in the brains of transgenic mice overexpressing heparanase (Hpa-tg). This study revealed that perivascular drainage was impeded in the Hpa-tg brain, evidenced by perivascular accumulation of the injected A beta in the thalamus of Hpa-tg mice. Furthermore, endogenous A beta accumulated at the perivasculature of Hpa-tg thalamus, but not in control thalamus. This perivascular clearance defect was confirmed following intracortical injection of dextran that was largely retained in the perivasculature of Hpa-tg brains, compared to control brains. Hpa-tg brains presented with thicker VBMs and swollen perivascular astrocyte endfeet, as well as elevated expression of the BBB-associated water-pump protein aquaporin 4 (AQP4). Elevated levels of both heparanase and AQP4 were also detected in human AD brain. These findings indicate that elevated heparanase levels alter the organization and composition of the BBB, likely through increased fragmentation of BBB-associated HS, resulting in defective perivascular drainage. This defect contributes to perivascular accumulation of A beta in the Hpa-tg brain, highlighting a potential role for heparanase in the pathogenesis of AD.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Keyword
- Perivascular drainage
- Heparan sulfate
- Heparanase
- Amyloid-beta
- Clearance
- Aging
- Alzheimer's disease
Publication and Content Type
- ref (subject category)
- art (subject category)
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To the university's database
- By the author/editor
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Zhang, Xiao
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O'Callaghan, Pau ...
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Li, Honglian
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Tan, Ying-Xia
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Zhang, Ganlin
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Barash, Uri
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show more...
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Wang, Xiaomin
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Lannfelt, Lars
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Vlodavsky, Israe ...
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Lindahl, Ulf
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Li, Jin-Ping
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Neurosciences
- Articles in the publication
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Acta neuropathol ...
- By the university
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Uppsala University