From metals to mitochondria: Linking trace elements to energy crisis in Alzheimer's disease.

Abstract

Alzheimer's disease (AD) is a chronic, progressive neurodegenerative disorder and the most common cause of dementia, with a high incidence in the global population, especially in the elderly. AD presents a complex pathogenesis including protein misfolding and aggregation, neuroinflammation, oxidative stress, mitochondrial dysfunction, and on. Currently, the imbalance of essential metals has been associated with AD pathology. Although trace elements such as iron (Fe), zinc (Zn), copper (Cu), and manganese (Mn) are vital for physiological processes in the brain, their dyshomeostasis, whether due to deficiency or excess, mainly impairs energy metabolism by increasing the production of free radicals (e.g., ROS), resulting in oxidative stress and, subsequent mitochondrial dysfunction. Excess metals impair the tricarboxylic acid (TCA) cycle and electron transport chain (ETC) in mitochondria. Thus, metal ions are closely linked to the mitochondrial energy-transducing capacity and redox homeostasis. The brain is highly susceptible and sensitive to metal-mediated metabolic crisis, leading to neuronal dysfunction, a key factor in the progression and severity of AD. Traditional treatments for AD pathology are based on acetylcholinesterase inhibitors and anti-amyloid approaches, but metal chelation has shown potential in reversing the clinical condition of the disease. Herein, we discuss the contribution of metal imbalance to the metabolic energy impairment of the brain in AD, highlighting its relationship with mitochondrial dysfunction. Some therapeutic approaches involving restoration of metal ion homeostasis are discussed.