Abstract
Accumulation of fibrillar amyloid β-protein (Aβ) in parenchymal plaques and in blood vessels of the brain, the latter condition known as cerebral amyloid angiopathy (CAA), are hallmark pathologies of Alzheimer's disease (AD) and related disorders. Cerebral amyloid deposits have been reported to accumulate various metals, most notably copper and zinc. Here we show that, in human AD, copper is preferentially accumulated in amyloid-containing brain blood vessels compared to parenchymal amyloid plaques. In light of this observation, we evaluated the effects of reducing copper levels in Tg2576 mice, a transgenic model of AD amyloid pathologies. The copper chelator, tetrathiomolybdate (TTM), was administered to twelve month old Tg2576 mice for a period of five months. Copper chelation treatment significantly reduced both CAA and parenchymal plaque load in Tg2576 mice. Further, copper chelation reduced parenchymal plaque copper content but had no effect on CAA copper levels in this model. These findings indicate that copper is associated with both CAA deposits and parenchymal amyloid plaques in humans, but less in Tg2576 mice. TTM only reduces copper levels in plaques in Tg2576 mice. Reducing copper levels in the brain may beneficially lower amyloid pathologies associated with AD.
Highlights
Cerebral amyloid angiopathy (CAA) is a common cerebral small vessel disease that involves the accumulation of amyloid protein (A ) primarily in small- and medium-sized arteries and arterioles of the meninges and cerebral cortex as well as along the capillaries of the cerebral microvasculature[1,2,3,4]
We sought to determine whether cerebral vascular amyloid deposits accumulate metal ions using the technique of x-ray fluorescence microscopy (XFM)
CAA is a common cerebral small vessel disease of the elderly and a prominent comorbidity of Alzheimer’s disease (AD) that promotes and exacerbates vascular-mediated cognitive impairment and dementia (VCID), yet our understanding of the condition remains limited. Both CAA and AD are characterized by the accumulation of fibrillar Aβ in the brain vessels and parenchyma, respectively
Summary
Cerebral amyloid angiopathy (CAA) is a common cerebral small vessel disease that involves the accumulation of amyloid protein (A ) primarily in small- and medium-sized arteries and arterioles of the meninges and cerebral cortex as well as along the capillaries of the cerebral microvasculature[1,2,3,4]. With the involvement of A , it is not surprising that CAA is a very common vascular comorbidity in patients with Alzheimer’s disease (AD)[3, 4]. CAA can uniquely contribute to the cognitive decline in VCID and AD in several ways. CAA promotes the increased expression and activation of certain proteolytic enzymes in cerebral vascular cells[11,12,13]. Together, these processes can lead to loss of vessel wall integrity and hemorrhage and/or chronic hypoperfusion and ischemic infarcts[2, 14,15,16,17,18]. The reasons why cerebral vascular amyloid develops and its contribution to downstream pathologies and VCID remain unclear
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
