Metallo-pathways to Alzheimer's disease: lessons from genetic disorders of copper trafficking

Abstract

Copper is an essential metal ion that provides catalytic function to numerous enzymes and also regulates neurotransmission and intracellular signaling. Conversely, a deficiency or excess of copper can cause chronic disease in humans. Menkes and Wilson disease are two rare heritable disorders of copper transport that are characterized by copper deficiency and copper overload, respectively. Changes to copper status are also a common feature of several neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). In the case of AD, which is characterized by brain copper depletion, changes in the distribution of copper has been linked with various aspects of the disease process; protein aggregation, defective protein degradation, oxidative stress, inflammation and mitochondrial dysfunction. Although AD is a multifactorial disease that is likely caused by a breakdown in multiple cellular pathways, copper and other metal ions such as iron and zinc play a central role in many of these cellular processes. Pioneering work by researchers who have studied relatively rare copper transport diseases has shed light on potential metal ion related disease mechanisms in other forms of neurodegeneration such as AD.

The interactome of the copper transporter ATP7A belongs to a network of neurodevelopmental and neurodegeneration factors

“…Along with the neurodegeneration characteristic of Menkes disease, disruptions in copper homeostasis have been implicated in several other prevalent neurodegenerative diseases, including Parkinson’s and Alzheimer’s disease (Greenough et al, 2016; Davies et al, 2016). There is evidence that therapeutic modulation of copper levels may be effective in alleviating symptoms of or delaying the onset of Parkinson’s and Alzheimer’s disease, yet there are gaps in our understanding of the regulation of copper homeostasis, particularly in the brain (Sparks and Schreurs, 2003; Brewer, 2015; Rose et al, 2011).…”

Alzheimer’s disease: How metal ions define β-amyloid function

“…After this assessment follows a review of the role of metal ions as probable age triggers of AD, with a main focus on how transition metal ions define the coordination chemistry, amyloid conformations, chemical properties and biological functions of Aβ and how these functions may be addressed in future therapeutic approaches. Since other reviews have covered the separate topics in extensive detail [34,38,[65][66][67][68][69][70][71][72][73][74], the purpose here is to provide a broader, up-to-date overview of these functions, including some controversies and particular attempts at unifying data. Special attention is also given to the normal and beneficial metal-Aβ interactions and their possible role in AD.…”

Copper in the suprachiasmatic circadian clock: A possible link between multiple circadian oscillators

“…Studies indicate that Cu accumulates in specific brain regions of aged subjects (Braidy et al., ; Fu, Jiang, & Zheng, ; Pushkar et al., ; Singh et al., ; Wang, Becker, et al., ; Zatta et al., ). In neurodegenerative diseases, long‐term Cu dyshomeostasis plays a role in oxidative damage, and redox‐active Cu accelerates formation of toxic oligomers associated with some neurodegenerative factors (e.g., Amyloid β, alpha synuclein) (Ahuja, Dev, Tanwar, Selwal, & Tyagi, ; Dell'Acqua et al., ; Greenough et al., ; Kawahara et al., ; Lan, Chen, Chai, & Hu, ; Okita et al., ; Squitti, ; Villar‐Pique et al., ). Thus, some circadian abnormalities observed in aged subjects and those with neurological diseases may involve Cu dyshomeostasis, an idea that warrants further study.…”

“…However, the intracellular concentration of unbound Cu is virtually zero in most cells under homeostatic conditions due to an abundance of proteins that bind Cu to protect against Cu‐induced ROS generation and oxidative stress (Hung, Bush, & Cherny, ). Systemic Cu deficiency, as occurs in Menkes disease, has moderate to severe effects on development and neurological function, and disruption of Cu delivery due to mutations, dietary deficiency, or chelation can lead to improper mitochondrial function, iron metabolism, and neuronal function (Greenough, Ramirez Munoz, Bush, & Opazo, ; Kawahara, Kato‐Negishi, & Tanaka, ; Medeiros, ; Opazo et al., ; Scheiber et al., ). Thus, cellular Cu homeostasis plays a significant role in modulating overall cellular metabolic activity.…”