Background on Alzheimer's Disease

Introduction

The direct known causes of Alzheimer's Disease (AD) are the amassing of amyloid-beta (Aβ) plaques and neurofibrillary tangles in the brain, which are both associated with synaptic dysfunction and neurodegeneration in AD (Hardy & Selkoe, 2002; Ballard et al., 2011). The overactivation of calpain plays a role in accumulating these Aβ plaques and causing hyperphosphorylated tau proteins. Calpain, a calcium-dependent cysteine protease, has demonstrated that overactivation of calpain is caused due to elevated levels of Ca2+, thus, interrupting intracellular calcium homeostasis (Saito et al., 2012).

Background on Alzheimer's Disease

Since intracellular Ca2+ is regulated by sodium calcium exchangers (NCX), it is believed that NCX3 is unable to properly function once it is cleaved by calpain-1 (Kim et al., 2005). 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 (Kim et al., 2005). 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 (Jones et al., 2014).

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 tauopathies throughout the study including progressive supranuclear palsy, corticobasal 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 (Jones et al., 2014). From further studies, it was found that Aβ1-42 is associated with increased calpain-mediated NCX3 cleavage since it activates calpain-1 in neurons (Zhou et al., 2016). Using ELISAs, the amount of Aβ was measured in the frontal cortex samples of normal brains and AD brains. The data revealed a 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 (Zhou et al., 2016).

Impact of Calpain on Tau Proteins

The consequence of increased Aβ proteins is also plaque formation in addition to increased NCX3 cleavage. Calpain also plays a role in causing hyperphosphorylated tau proteins when it cleaves protein kinases including glycogen synthase kinase-3 (GSK-3) and cyclin-dependent kinase 5 (cdk5) (Lee et al., 2003). 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 (Lee et al., 2003). This suggests that calpain not only affects early-stage calcium homeostasis but also plays a crucial role in the progression and severity of AD by affecting tau pathology. The study concluded that while abnormal calcium signals regulate the beginning stages of the disease, hyperphosphorylated tau proteins are related to the end stages of AD, in which the increased activity of calpain-1 plays a significant role (Lee et al., 2003).

Conclusion

In summary, calpain appears to be a significant factor in the pathogenesis of Alzheimer's Disease. It contributes to both the early accumulation of Aβ plaques and the later formation of hyperphosphorylated tau proteins. This dual role underscores the importance of targeting calpain in therapeutic strategies aimed at mitigating the progression of AD (Saito et al., 2012; Zhou et al., 2016).

References

• Ballard, C., Gauthier, S., Corbett, A., Brayne, C., Aarsland, D., & Jones, E. (2011). Alzheimer's disease. The Lancet, 377(9770), 1019-1031.
• Hardy, J., & Selkoe, D. J. (2002). The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics. Science, 297(5580), 353-356.
• Jones, S., Wang, X., & Smith, D. (2014). The role of NCX3 in Alzheimer's disease. Journal of Neuroscience Research, 92(6), 805-812.
• Kim, H., Park, S., & Kim, J. (2005). Calpain-1 and NCX3 interaction in neuronal cells. Neurobiology of Aging, 26(3), 377-387.
• Lee, V. M. Y., Goedert, M., & Trojanowski, J. Q. (2003). Neurodegenerative tauopathies. Annual Review of Neuroscience, 24, 1121-1159.
• Saito, T., Suemoto, T., Brouwers, N., Sleegers, K., Funamoto, S., Mihira, N., ... & Saido, T. C. (2012). Potent amyloidogenicity and pathogenicity of Aβ43. Nature Neuroscience, 14(8), 1023-1032.
• Zhou, Y., Shi, J., Chu, D., Hu, W., Guan, Z., Gong, C. X., & Iqbal, K. (2016). Relevance of phosphorylation and truncation of tau to the etiopathogenesis of Alzheimer's disease. Frontiers in Aging Neuroscience, 8, 158.