Introduction. Alzheimer’s Disease (AD) is a chronic neurodegenerative disorder involving atrophy of the cerebral cortex1,2. Patients initially present clinically with prior onset dementia that typically leads to severe memory less and other cognitive deficits3. Past studies characterized Alzheimer’s Disease pathology by the accumulation of tau protein neurofibrillary tangles (NFTs) within the cell4. Recent studies state tau pathology is due to the prefibrillar aggregates i.e. tau oligomers that form prior to the tangles4. It has been seen that with Alzheimer’s Disease, there are quadruple the amount of tau oligomers present in the brain4. From this newfound line of thinking has come the idea that the reason these aggregates form in Alzheimer’s patients is due to the hyperphosporylation of tau proteins via multiple kinases of different pathways4. These findings have led to a new line of targeted AD therapeutic research. Methods. Four different therapies were studied. Different models were used for each study. In each study, tau hyperphosphorylation was analyzed via Western blot analysis. Excluding the SLM study (use of SH-SY5Y cells), cortex and hippocampal samples from the respective mice models were used during analysis. From the Western blots, statistical calculations compared the levels of phosphorylated tau relative to dephosphorylated tau in AD+treatment, AD, and wild type mice at varying Serine and Threonine domains of tau. Morris Water Maze and Shuttle Box avoidance tests were conducted during two of the therapies to identify the presence of any increase in cognitive ability. Results. The 3 mice therapies all showed decreased hyperphosphorylation of tau in the cortex and hippocampus, while actual levels of total tau protein itself were only decreased when treatment with Selenomethionine was administered5-7. The decreased hyperphosphorylation was due to phosphorylation/inhibition of kinases including glycogen synthase kinase-3 beta (GSK-3β), and cyclin-dependent kinase 5 (CDK5)4-7. The protective therapeutic effects did yield measured improvements in cognition via the Morris Water Maze for Liraglutide and the CDK5 adenovirus6,7. The virus therapy also showed measured improvement upon Shuttle Box testing. The SH-SY5Y (SLM) cell study is promising as it also exhibited a reduction in hyperphosphorylated tau, but now has to actually be studied in AD patients8. Conclusions. Studies have found that tau prefibrillar aggregates are prevalent in Alzheimer’s Disease and amplified due to tau hyperphosphorylation at the protein’s varying afflicted Serine/Threonine domains. Therapies are targeting the hyperphosphorylative process in order to treat Alzheimer’s Disease and hopefully regain cognitive abilities by focusing on inhibiting GSK-3β and CDK5.
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- Himmelstein DS, Ward SM, Lancia JK, Patterson KR, Binder LI. Tau as a therapeutic target in neurodegenerative disease. Pharmacology & therapeutics. 2012;136(1):8-22. doi:10.1016/j.pharmthera.2012.07.001.
- Zhang Z, Wu Q, Zheng R, et al. Selenomethionine mitigates cognitive decline by targeting both tau hyperphosphorylation and autophagic clearance in an alzheimer’s disease mouse model. The Journal of Neuroscience. 2017:3229.doi: 10.1523/JNEUROSCI.3229-16.2017.
- Qi L, Chen Z, Wang Y, et al. Subcutaneous liraglutide ameliorates methylglyoxal-induced Alzheimer-like tau pathology and cognitive impairment by modulating tau hyperphosphorylation and glycogen synthase kinase-3β. American Journal of Translational Research. 2017;9(2):247-260.
- Yong H, Pan S, Xu M, et al. Adeno-associated viral 9–mediated Cdk5 inhibitory peptide reverses pathologic changes and behavioral deficits in the Alzheimer’s disease mouse model. The Faseb Journal. 2017;31:1-11. doi: 10.1096/fj.201700064R.
- Wu X, Kosaraju J, Tam KY. SLM, a novel carbazole-based fluorophore attenuates okadaic acid-induced tau hyperphosphorylation via down-regulating GSK-3β activity in SH-SY5Y cells. European Journal of Pharmaceutical Sciences. doi: 10.1016/j.ejps.2017.03.037.