Copper and Zinc Dysregulation in Alzheimer's Disease. (December 2018)

• Record Type: Journal Article
• Authors: Sensi, Stefano L.; Granzotto, Alberto; Siotto, Mariacristina; Squitti, Rosanna
• Is Part Of: Trends in pharmacological sciences. Volume 39:Number 12(2018)
• Page Start: 1049
• Page End: 1063
• Publication Date: 2018-12
• Subjects: ceruloplasmin -- Wilson's disease -- amyloid -- excitotoxicity -- BDNF -- synaptic plasticity; Pharmacology -- Periodicals; Pharmacology -- trends -- Periodicals; Pharmacologie -- Périodiques; Pharmacology; Electronic journals; Periodicals; 615.1
• DOI: 10.1016/j.tips.2018.10.001
• Languages: English
• ISSNs: 0165-6147

Abstract

Abstract : Alzheimer's disease (AD) is one of the most common forms of dementia. Despite a wealth of knowledge on the molecular mechanisms involved in AD, current treatments have mainly focused on targeting amyloid β (Aβ) production, but have failed to show significant effects and efficacy. Therefore, a critical reconsideration of the multifactorial nature of the disease is needed. AD is a complex multifactorial disorder in which, along with Aβ and tau, the convergence of polygenic, epigenetic, environmental, vascular, and metabolic factors increases the global susceptibility to the disease and shapes its course. One of the cofactors converging on AD is the dysregulation of brain metals. In this review, we focus on the role of AD-related neurodegeneration and cognitive decline triggered by the imbalance of two endogenous metals: copper and zinc. Highlights: Alzheimer's disease (AD) is a widespread neurodegenerative condition that affects approximately 50 million people worldwide. Costs for disease management are predicted to reach US$1 trillion in 2018 and are expected to double by the year 2030. Around the world, one new AD case is diagnosed every 3 s. No disease-modifying strategies are available. The AD epidemic calls for a full investigation of novel disease mechanisms and targets. The current AD drug development pipeline has centered around the amyloid cascade hypothesis. The approach has not paid off, and it is now time to recognize the multifactorial nature of the disease and expand the spectrum of intervention. A more effective approach should also consider the possibility of patient stratification in different subtypes and targeted interventions. The dysregulation of metal ions in the brain is emerging as a comorbidity factor in subsets of patients with AD. Dysregulation of copper (Cu) is found in a subgroup of patients with AD and negatively shapes the course of the disease. Brain zinc participates in AD pathogenesis by affecting amyloid metabolism, but the metal can also positively modulate synaptic functioning and neurotrophic signaling, as well as help to restore copper homeostasis.