Background on Alzheimer's Disease

The direct known causes of AD are the amassing of Aβ plaques and neurofibrillary tangles in the brain, which are both associated with synaptic dysfunction and neurodegeneration in AD. The over activation of calpain plays a role in accumulating these Aβ plaques and causing hyper phosphorylated tau proteins. Calpain, a calcium dependent cysteine protease, has demonstrated that over activation of calpain is caused due to elevated levels of Ca2+, thus, interrupting intracellular calcium homeostasis.

Since intracellular Ca2+ are regulated by sodium calcium exchangers (NCX), it is believed that NCX3 are unable to properly function once they are cleaved by calpain-1 6. This is because calpain prevents Ca2+ from binding to the NCX regulatory domain. As a result, calcium concentrations are elevated in the intraneuronal cells leading to neurotoxicity 6. To support this explanation, a study was conducted using western blotting of postmortem human brain comparing the full length and cleaved NCX3 amounts, using the full length as a control.

The results from the study demonstrated from a box plot of the amount of calpain cleaved/total NCX3, showed an increase in the amount of calpain that was cleaved in AD. This was compared to other auxopathies throughout the study including progressive pronuclear palsy, cortices degeneration, and frontotemporal dementia, of which only AD showed elevated amounts of calpain cleaved to NCX3. It was concluded from the results of this study that indeed calpain activity increased when it is cleaved to NCX3, resulting in the disruption of the ion exchanger that abnormally regulates Ca2+ levels in AD. From further studies, it was found that Aβ1-42 is associated with increased calpain mediated NCX3 cleavage since it activates calpain-1 in neurons. Using ELISAs, the amount of Aβ were measured in the frontal cortex samples of normal brains and AD brains. The data revealed strong correlation between the amount of Aβ1-42 levels and calpain cleaved NCX3, showing that high levels of Aβ are also responsible for the increased NCX3 cleavage seen in AD brains.

The consequence of increased Aβ proteins is also plaque formation in addition to increased NCX3 cleavage. Calpain also plays a role in causing hyper phosphorylated 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 relations between calpain, tau kinases, and synaptic proteins in the end stages of AD. The study demonstrated increased levels of calpain-1 activity as well as of tau kinases, GSK-3, and cdk5 in the end stages of AD, causing a loss of synaptic function and fibrils in the brain. The study concluded that while abnormal calcium signals regulate the beginning stages of the disease, hyper phosphorylated tau proteins are related to the end stages of AD, in which the increased activity of calpain-1 plays a significant role.