Alzheimer’s disease (AD) is characterized by the presence of senile plaques and neurofibrillary tangles in the neocortex and hippocampus of AD patients. In addition, a marked decrease in synaptic contacts has been detected in these affected brain areas. Due to its prevalence in the aging population, this disease has been the focus of numerous studies. The data obtained from those studies suggest that the mechanisms leading to the formation of the hallmark lesions of AD might be linked. One of such mechanisms seems to be the dysregulation of calcium homeostasis that results in the abnormal activation of calpains. Calpains are a family of Ca2+-dependent cysteine proteases that play a key role in multiple cell functions including cell development, differentiation and proliferation, axonal guidance, growth cone motility, and cell death, among others. In this paper, we briefly reviewed data on the structure of these proteases and their regulation under normal conditions. We also summarized data underscoring the participation of calpains in the neurodegenerative mechanisms associated with AD. 1. Introduction Alzheimer’s disease (AD) is the most common cause of dementia in the aging population. This disease develops over time and leads to significant cognitive deficits affecting memory, insight, judgment, abstraction, and language functions [1]. AD affects more than 5 million people in the United States and this number is projected to rise to 35 million by 2050 [2, 3]. This estimate underscores both the scope of this health care issue for the society as a whole and the need for the development of therapeutic options for these patients. The diagnosis of this neurodegenerative disease relies on the presence of senile plaques and neurofibrillary tangles in affected brain areas at autopsy. These AD hallmark lesions are the results of the pathological deposition of proteins normally present throughout the brain. Senile plaques are composed of extracellular deposits of beta-amyloid (Aβ) derived by proteolytic cleavage from the amyloid precursor protein (APP) [4–10]. Neurofibrillary tangles, on the other hand, are intracellular bundles of self-assembled tau proteins [11–38]. The formation of both senile plaques and neurofibrillary tangles is associated with progressive and irreversible degeneration of neuronal processes and the loss of synaptic connections [39–50]. Initially, multiple studies focused on defining the characteristics of AD and on the analysis of the composition of senile plaques and neurofibrillary tangles. More recently, data have been obtained on the
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