Calcium Ions Aggravate Alzheimer’s Disease Through the Aberrant Activation of Neuronal Networks, Leading to Synaptic and Cognitive Deficits

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease that is characterized by the production and deposition of β-amyloid protein (Aβ) and hyperphosphorylated tau, leading to the formation of β-amyloid plaques (APs) and neurofibrillary tangles (NFTs). Although calcium ions (Ca2+) promote the formation of APs and NFTs, no systematic review of the mechanisms by which Ca2+ affects the development and progression of AD has been published. Therefore, the current review aimed to fill the gaps between elevated Ca2+ levels and the pathogenesis of AD. Specifically, we mainly focus on the molecular mechanisms by which Ca2+ affects the neuronal networks of neuroinflammation, neuronal injury, neurogenesis, neurotoxicity, neuroprotection, and autophagy. Furthermore, the roles of Ca2+ transporters located in the cell membrane, endoplasmic reticulum (ER), mitochondria and lysosome in mediating the effects of Ca2+ on activating neuronal networks that ultimately contribute to the development and progression of AD are discussed. Finally, the drug candidates derived from herbs used as food or seasoning in Chinese daily life are summarized to provide a theoretical basis for improving the clinical treatment of AD.

Inflammation context in Alzheimer’s disease, a relationship intricate to define

“…Though it is not yet entirely understood how these toxic oligomers perform their activity [63], they have been associated with several microglial and astrocytic membrane proteins. Many of these receptors, including N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, cause a fast influx of Ca 2+ , triggering inflammation [65][66][67]. In addition, Aβ can also bind the receptor for advanced glycation end products (RAGE), a surface molecule found in microglia, astrocytes, and cerebral endothelial cells, which mediates immune responses [68].…”

Patient-Specific iPSCs-Based Models of Neurodegenerative Diseases: Focus on Aberrant Calcium Signaling

“…It should also be noted that mitochondrial dysfunction is closely related to aberrant calcium signaling, as mitochondria are stores of calcium in cells, and excessive calcium uptake can lead to mitochondria overload, caspase activation, and apoptosis. The major organelles that maintain calcium homeostasis in cell mitochondria and the ER also play a critical role in oxidative stress [ 74 , 75 ], neuroinflammation [ 83 , 84 ], and apoptosis [ 84 ]. Thus, alterations in the production of reactive oxygen species that can lead to ER stress should also be addressed in studies of aberrant calcium signaling.…”

Sec61 complex/translocon: The role of an atypical ER Ca2+-leak channel in health and disease

“…Obvious possible candidates include neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and Creutzfeld-Jacob disease. The role of intracellular Ca 2+ in general and of ER Ca 2+ in particular (Ureshino et al, 2019;da Costa et al, 2020;Lim et al, 2021;Callens et al, 2021;Kovacs et al, 2021;Guan et al, 2021;Huang et al, 2022;Ge et al, 2022;Kim et al, 2022) as well as of ER stress and accumulation of misfolded proteins (da Costa et al, 2020;Guan et al, 2021;Kim et al, 2022;Ren et al, 2021;Yasmeen et al, 2022;Shacham et al, 2019;Chakraborty et al, 2005) have indeed already been demonstrated in several neurodegenerative diseases.…”