Novel Protein Kinase Inhibitors Related to Tau Pathology Modulate Tau Protein-Self Interaction Using a Luciferase Complementation Assay

Abstract

The current number of drugs available for the treatment of Alzheimer’s disease (AD) is strongly limited and their benefit for therapy is given only in the early state of the disease. An effective therapy should affect those processes which mainly contribute to the neuronal decay. There have been many approaches for a reduction of toxic Aβ peptides which mostly failed to halt cognitive deterioration in patients. The formation of neurofibrillary tangles (NFT) and its precursor tau oligomers have been suggested as main cause of neuronal degeneration because of a direct correlation of their density to the degree of dementia. Reducing of tau aggregation may be a viable approach for the treatment of AD. NFT consist of hyperphosphorylated tau protein and tau hyperphosphorylation reduces microtubule binding. Several protein kinases are discussed to be involved in tau hyperphosphorylation. We developed novel inhibitors of three protein kinases (gsk-3β, cdk5, and cdk1) and discussed their activity in relation to tau phosphorylation and on tau–tau interaction as a nucleation stage of a tau aggregation in cells. Strongest effects were observed for those inhibitors with effects on all the three kinases with emphasis on gsk-3β in nanomolar ranges.

When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer’s and Huntington’s Disease

“…CDK1 can phosphorylate Aβ at Ser26 increasing its neurotoxicity and reducing its ability to form insoluble fibrils [ 391 , 392 ]. CDK1 and CDK2 also contribute to Tau hyperphosphorylation [ 201 , 393 , 394 , 395 , 396 ]. In cell culture experiments, toxicity by Aβ was shown to involve induction of CDK2 activity and its phosphorylation of Tau [ 397 ] ( Figure 1 C)…”

Synthesis, Antibacterial Activity, and Structure–Activity Relationship of Fusaric Acid Analogs

“…FA analogs 17 and 18 were synthesized via the Williamson ether synthesis of 15 and 16 with alkyl/aromatic halide followed by sodium hydroxide mediated hydrolysis (Scheme 3). 22 Compounds 20–22 were obtained from 19 by an alkylation or amidation (Scheme 4) with alkyl halide, acyl chloride, or sulfonyl chloride 23–25 …”

GSK3β and Tau Protein in Alzheimer’s Disease and Epilepsy

“…Interestingly, the efficacy of various antiepileptic drugs (AEDs) has been tested in epilepsy experimental models and in AD patients, showing a promising function in cognitive impairment prevention (Sánchez et al, 2018). Since tau hyperphosphorylation is the main mechanism responsible for NFT formation, it has been suggested that inhibiting different tau kinases such as CDK5 and GSK3β, involved in tau hyperphosphorylation, could reduce their aggregation (Xie et al, 2017;Holzer et al, 2018), observed in AD (Morris et al, 2011) and epilepsy (Sen et al, 2007;Thom et al, 2011;Tai et al, 2016).…”