Low levels of copper disrupt brain amyloid-β homeostasis by altering its production and clearance

Abstract

Significance The causes of the sporadic form of Alzheimer’s disease (AD) are unknown. In this study we show that copper (Cu) critically regulates low-density lipoprotein receptor-related protein 1–mediated Aβ clearance across the blood–brain barrier (BBB) in normal mice. Faulty Aβ clearance across the BBB due to increased Cu levels in the aging brain vessels may lead to accumulation of neurotoxic Aβ in brains. In a mouse model of AD low levels of Cu also influences Aβ production and neuroinflammation. Our study suggests that Cu may also increase the severity of AD.

Biological metals and metal-targeting compounds in major neurodegenerative diseases

“…62 A marked elevation of copper in brain capillaries isolated from aged mice has been described, which may adversely impact on the clearance of Ab (see below). 63 A similar marked elevation of copper has been found in the subventricular zone of aged rats, associated with decreased neurogenesis. 64 However, with advanced aging in humans (after the age of 50), levels of brain cortical copper decline markedly, 65 potentially promoting Ab amyloidogenesis, 66-68 as discussed below.…”

“…100 The expression of low density lipoprotein receptor-related protein 1 (LRP1) in the brain microvasculature, and associated clearance of Ab from the brain, has been recently reported to be very sensitive to copper. 63 Treatment with low levels of Cu in drinking water for 90 days was sufficient to selectively reduce LRP1 and Ab clearance. Indeed, treatment with very low levels of Cu 2+ (200 nM) suppressed LRP1 levels in cultured primary mouse brain endothelial cells through oxidative stress, and the same levels of Al 3+ , Zn 2+ , or Fe 2+ had no effect.…”

Antidiabetic drugs restore abnormal transport of amyloid-β across the blood–brain barrier and memory impairment in db / db mice

“…The unfiltered microvessels were harvested by washing into a low binding tube and resuspended in ice-cold buffered solution. The microvessels were then washed three times with 1.5 ml ice-cold buffered solution and then resuspended in ice-cold lysis buffer, sonicated, centrifuged at 20,000 g for 20 min, and supernatant was used for Western blot analysis (Singh et al, 2013).…”

Copper is an endogenous modulator of neural circuit spontaneous activity

“…As such, copper has been historically regarded as a tightly sequestered cofactor that must be buried within protein active sites to protect against reactive oxygen species generation and subsequent free radical damage chemistry. Indeed, elegant work continues to identify molecular players that maintain copper homeostasis in the brain (7,8) and related organs (9)(10)(11), and loss of this strict regulation is implicated in neurotoxic stress (12)(13)(14) and a variety of neurodegenerative and neurodevelopmental disorders including Menkes (15,16) and Wilson's (17) diseases, familial amyotrophic lateral sclerosis (18,19), Alzheimer's (6,14,(20)(21)(22) and Huntington's (23, 24) diseases, and prion-mediated encephalopathies (14,25,26).…”