The known direct causes of AD are the accumulation of Aβ plaques and neurofibrillary tangles in the brain, both associated with synaptic dysfunction and neurodegeneration in AD. Excessive calpain activation plays a role in the accumulation of these Aβ plaques and causing hyperphosphorylated tau proteins. Calpain, a calcium-dependent cysteine ​​protease, has shown that excessive calpain activation is caused by elevated Ca2+ levels, thus disrupting intracellular calcium homeostasis. Say no to plagiarism. Get a tailor-made essay on "Why Violent Video Games Shouldn't Be Banned"? Get an original essay Since intracellular Ca2+ is regulated by sodium-calcium exchangers (NCXs), NCX3s are thought to be unable to function properly once cleaved by calpain -1 6. This is because calpain prevents Ca2+ from binding to the domain NCX regulator. Consequently, calcium concentrations are elevated in intraneuronal cells leading to neurotoxicity 6. To support this explanation, a study was conducted using western blotting of postmortem human brain comparing the amounts of full-length and cleaved NCX3, using l 'full length as control. The results of the study, demonstrated by a box plot of the amount of cleaved calpain/total NCX3, showed an increase in the amount of cleaved calpain in AD. This was compared to other auxopathies during the study, including progressive pronuclear palsy, degeneration of the cortices, and frontotemporal dementia, of which only AD showed elevated amounts of NCX3-cleaved calpain. From the results of this study it was concluded that calpain activity actually increases when it is cleaved in NCX3, resulting in disruption of the ion exchanger that abnormally regulates Ca2+ levels in AD. From further studies, Aβ1-42 was found to be associated with increased calpain-mediated NCX3 cleavage as it activates calpain-1 in neurons. Using ELISAs, the amount of Aβ was measured in frontal cortex samples from normal brains and AD brains. The data revealed a strong correlation between the amount of Aβ1-42 levels and calpain cleaved in NCX3, demonstrating that high levels of Aβ are also responsible for the increased NCX3 cleavage observed in AD brains. Please note: this is just a sample. Request an article customization now from our expert writers. Get a Custom Assay The consequence of increased Aβ proteins is also the formation of plaques in addition to increased NCX3 cleavage. Calpain also plays a role in causing hyperphosphorylation of tau proteins when it cleaves protein kinases including glycogen kinase synthase-3 (GSK-3) and cyclin-dependent kinase 5 (cdk5). To support this claim, a study was conducted on postmortem brains that showed changes and relationships between calpain, tau kinase, and synaptic proteins in the final stages of AD. The study demonstrated increased activity levels of calpain-1 and tau kinases, GSK-3 and cdk5 in the final stages of AD, causing a loss of synaptic function and fibrils in the brain. The study concluded that while abnormal calcium signals regulate the early stages of the disease, hyperphosphorylated tau proteins are related to the late stages of AD, in which increased calpain-1 activity plays a significant role.