Despite decades of research and effort, there is still no effective disease-modifying treatment
for Alzheimer’s Disease (AD). Most of the recent AD clinical trials were targeting amyloid pathway, but
all these trials failed. Although amyloid pathology is a hallmark and defining feature of AD, targeting
the amyloid pathway has been very challenging due to low efficacy and serious side effects. Alternative
approaches or mechanisms for our understanding of the major cause of memory loss in AD need to be
considered as potential therapeutic targets. Increasing studies suggest that Ca2+ dysregulation in AD
plays an important role in AD pathology and is associated with other AD abnormalities, such as excessive
inflammation, increased ROS, impaired autophagy, neurodegeneration, synapse, and cognitive dysfunction.
Ca2+ dysregulation in cytosolic space, Endoplasmic Reticulum (ER) and mitochondria have
been reported in the context of various AD models. Drugs or strategies, to correct the Ca2+ dysregulation
in AD, have been demonstrated to be promising as an approach for the treatment of AD in preclinical
models. This review will discuss the mechanisms of Ca2+ dysregulation in AD and associated pathology
and discuss potential approaches or strategies to develop novel drugs for the treatment of AD by targeting
Keywords: Alzheimer's disease, calcium hypothesis, nSOCE, therapeutic agents, cytosolic space, endoplasmic reticulum (ER).
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