Novel Protein Kinase Inhibitors Related to Tau Pathology Modulate Tau Protein-Self Interaction Using a Luciferase Complementation Assay.
Max HolzerNico SchadeAnsgar OpitzIsabel HilbrichJens StielerTim VogelValentina NeukelMoritz OberstadtFrank TotzkeChristoph SchächteleWolfgang SipplAndreas HilgerothPublished in: Molecules (Basel, Switzerland) (2018)
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.
Keyphrases
- cerebrospinal fluid
- binding protein
- protein protein
- end stage renal disease
- protein kinase
- amino acid
- cognitive decline
- cell proliferation
- small molecule
- stem cells
- high throughput
- oxidative stress
- mild cognitive impairment
- peritoneal dialysis
- cell cycle
- induced apoptosis
- bone marrow
- cognitive impairment
- ejection fraction
- smoking cessation
- single cell
- mesenchymal stem cells
- endoplasmic reticulum stress
- cell therapy