Role of Mitochondrial Calcium Dysregulation in Alzheimer's Disease Pathogenesis

Mitochondrial calcium has emerged as a critical player in Alzheimer's disease (AD), closely linked to neuronal dysfunction and cognitive decline seen in patients. Intracellular calcium signaling is essential for processes like synaptic plasticity, neuronal survival, and differentiation. When this balance is disturbed, it can trigger early pathological changes in AD, including the accumulation of amyloid-β (Aβ) peptides and the development of neurofibrillary tangles (NFTs), the hallmark features of the disease. Calcium imbalance in mitochondria disrupts their function, leading to reduced adenosine triphosphate (ATP) production, increased reactive oxygen species (ROS), and ultimately neuronal death. Aβ and tau act synergistically to further disturb calcium regulation, intensifying neurodegeneration. Excess mitochondrial calcium is also linked to altered activity of key calcium transporters, such as the mitochondrial calcium uniporter (MCU) and sodium/calcium/lithium exchanger (NCLX). Moreover, several genetic risk factors for AD, including ApoE4, PS1, PS2, and CALHM1, are known to influence intracellular calcium homeostasis. Building on this, the present study investigates how calcium dysregulation impairs mitochondrial function in AD. Understanding the mechanisms of calcium-induced mitochondrial dysfunction and identifying potential targets to control mitochondrial calcium levels could provide valuable insights for developing therapies against AD and other neurodegenerative diseases.