The Role of Copper in Cerebral Amyloid Angiopathy

Project: Research projectResearch Project

Description

Vascular cognitive impairment & dementia (VCID) is defined as a form of dementia that is triggeredby damage to cerebral blood vessels or cerebrovascular disease. Cerebral amyloid angiopathy (CAA),which is accumulation of amyloid ß-protein (Aß) within and along primarily small and medium-sizedarteries and arterioles of the brain and in the cerebral microvasculature, is a common cerebral vascularcondition that can cause VCID in the elderly. Not surprisingly, with the involvement of Aß, CAA is themost common vascular comorbidity found in the brains of Alzheimer's disease (AD) patients. Althoughthere is evidence that both parenchymal plaque amyloid and cerebral microvascular amyloid cancontribute to dementia in patients with AD and related disorders, there is growing recognition that thelatter is a potent driver of cognitive impairment. Yet, the reasons as to why cerebral vascularamyloid forms and its contribution to downstream pathologies and early cognitive impairmentremain unclear. Altered copper homeostasis has been considered an important factor in the neurodegenerativediseases. Earlier findings suggest that copper may play an important role in the formation of amyloiddeposits and in subsequent neuronal dysfunction and cognitive impairment. However, relatively littleis known about the accumulation of copper in cerebral vascular amyloid deposits, which areassociated with early-onset VCID. Thus, the overall hypothesis of our proposal is that copper playsa role in driving fibrillar amyloid assembly in CAA and that the subsequent accumulation ofcopper in the cerebrovascular amyloid deposits promotes downstream pathologies and early-onset cognitive impairment. In order to test this hypothesis we propose to three specific aims. First,we will determine if vascular amyloid deposits exhibit high levels of copper compared to parenchymalamyloid plaques in post mortem human brain tissue samples of AD, sporadic CAA and familial CAApatients and in transgenic mouse models. Second, we will investigate the effects of copper on Aß fibrilassembly. Third, we will determine the effects of increasing or reducing copper levels on thedevelopment of CAA, downstream pathologies and cognitive impairment in Tg-SwDI mice. Currently, there are no effective therapies or reliable biomarkers specifically for CAA. Thesedeficiencies are complicated by our lack of understanding of the assembly and unique structuralattributes of cerebral vascular amyloid and their distinctive features that lead to CAA formation andsubsequent pathologies. The present proposal, focused on the role of copper in these events, will seekto fill this critical void in our knowledge and will advance our understanding of the pathogenesis of CAAand provide insight into the development of novel diagnostic markers and potential therapeuticinterventions for CAA and VCID.
StatusActive
Effective start/end date7/1/164/30/21

Funding

  • National Institutes of Health: $395,000.00

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Cerebral Amyloid Angiopathy
Copper
Blood Vessels
Amyloid Plaques
Amyloidogenic Proteins
Amyloid
Pathology
Dementia
Alzheimer Disease
Cerebrovascular Disorders
Hematologic Diseases
Brain
Arterioles
Brain Diseases
Microvessels
Transgenic Mice
Comorbidity
Homeostasis
Biomarkers
Cognitive Dysfunction