Abstract
Blood-brain barrier (BBB) defects and cerebrovascular dysfunction contribute to amyloid-β (Aβ) brain accumulation and drive Alzheimer disease (AD) pathology. By regulating vascular functions and inflammation in the microvasculature, a disintegrin and metalloprotease with thrombospondin type I motif, member 13 (ADAMTS13) plays a significant protective effect in atherosclerosis and stroke. However, whether ADAMTS13 influences AD pathogenesis remains unclear. Using in vivo multiphoton microscopy, histological, behavioral, and biological methods, we determined BBB integrity, cerebrovascular dysfunction, amyloid accumulation, and cognitive impairment in APPPS1 mice lacking ADAMTS13. We also tested the impact of viral-mediated expression of ADAMTS13 on cerebrovascular function and AD-like pathology in APPPS1 mice. We show that ADAMTS13 deficiency led to an early and progressive BBB breakdown as well as reductions in vessel density, capillary perfusion, and cerebral blood flow in APPPS1 mice. We found that deficiency of ADAMTS13 increased brain plaque load and Aβ levels and accelerated cerebral amyloid angiopathy (CAA) by impeding BBB-mediated clearance of brain Aβ, resulting in worse cognitive decline in APPPS1 mice. Virus-mediated expression of ADAMTS13 attenuated BBB disruption and increased microvessels, capillary perfusion, and cerebral blood flow in APPPS1 mice already showing BBB damage and plaque deposition. These beneficial vascular effects were reflected by increase in clearance of cerebral Aβ, reductions in Aβ brain accumulation, and improvements in cognitive performance. Our results show that ADAMTS13 deficiency contributes to AD cerebrovascular dysfunction and the resulting pathogenesis and cognitive deficits and suggest that ADAMTS13 may offer novel therapeutic opportunities for AD.
Highlights
Alzheimer disease (AD) is associated with distinct cerebrovascular abnormalities and cerebral accumulation of amyloid-β peptide (Aβ) [1,2]
Immunoblot analyses with the antibody that recognizes both human and mouse amyloid precursor protein (APP) indicated a marked increase in APP protein expression in the brains of transgenic mice compared with nontransgenic mice (S1B Fig)
Disruption of ADAMTS13 was confirmed by PCR (S1D Fig), and ADAMTS13 mRNA was detected by reverse transcription-Polymerase Chain Reaction (RT-PCR) in the liver of wild type (WT) and APPPS1 mice but not in APPPS1–Adamts13−/− mice (S1E Fig)
Summary
Alzheimer disease (AD) is associated with distinct cerebrovascular abnormalities and cerebral accumulation of amyloid-β peptide (Aβ) [1,2]. ADAMTS13 deficiency results in ultralarge VWF (UL-VWF) multimers in the circulation, causing vascular dysfunction and inflammation in the microvasculature [9,10]. A reduced plasma ADAMTS13 activity and increased VWF levels are associated with an increased risk of cardiovascular and cerebrovascular diseases, such as atherosclerosis, stroke, and vascular remodeling [11,12,13,14]. VWF was reported to release upon endothelium injury and promote vascular leakage [15,16], whereas ADAMTS13 protected the BBB integrity by enhancing VWF cleavage [16,17]. Whether the ADAMTS13-VWF axis can modulate cerebrovascular functions influencing AD pathology remains unclear
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