Taken together, our findings suggest that GRK5 deficiency contributes to the pathogenesis of Alzheimer's disease by influencing the hyperphosphorylation of tau through the activation of GSK3β.
In AD, GSK-3β plays an important role in hyperphosphorylation of microtubule-associated protein tau (tau), which is one of the pathological features in AD.
We conclude that lymphocytes from young, non-demented persons carrying the ApoE 4/4 genotype show molecular changes that are involved in specific processes associated with the pathophysiology of AD such as increased phosphorylation of tau or increased expression of stress-related proteins like calcineurin, GSK3β, or RCAN1.
Accumulative evidence demonstrates that GSK-3β inactivation may be potentially developed as the promising strategy in management of many diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD).
7-bromoindirubin-3-oxime (7Bio), an indirubin derivative derived from indirubin-3-oxime, possesses inhibitory effects against cyclin-dependent kinase-5 (CDK5) and glycogen synthase kinase-3β (GSK3β), two pharmacological targets of Alzheimer's disease (AD).
More importantly, persistent activation of Wnt signaling through Wnt ligands, or inhibition of negative regulators of Wnt signaling, such as Dickkopf-1 (DKK-1) and glycogen synthase kinase-3 β (GSK-3 β ) that are hyperactive in the disease state, is able to protect against A β toxicity and ameliorate cognitive performance in AD.
These findings suggest that truncation of GSK-3β by Ca(2+)/calpain I markedly increases its activity and involvement of this mechanism probably is responsible for up-regulation of GSK-3β and consequent abnormal hyperphosphorylation of tau and neurofibrillary degeneration in AD.
Glycogen synthase kinase 3β (GSK-3β) is a widely investigated molecular target for numerous diseases including Alzheimer's disease, cancer, and diabetes mellitus.
This study is the first to demonstrate a transient increase in phosphor-Tau caused by PKA, but not GSK3β, in the CSF and induced pluripotent stem cells (iPSCs) of AD, implying that both GSKIP and GSK3β function as anchoring proteins to strengthen the cAMP/PKA/Tau axis signaling during AD pathogenesis.
Thus, bergenin was screened by molecular docking study using GOLD suite (version 5.2), CCDC for predicting its activity against targets of AD management like acetylcholinesterase (AChE) (1B41), butyrylcholinesterase (BuChE) (1P0I), Tau protein kinase 1 (GSK-3β) (1J1B), BACE-1 (1FKN) wherein the GOLD score and fitness of bergenin were comparable to those of standard drugs like donepezil, galanthamine, physostigmine, etc.
Taken together, these data indicate that GSK-3β is crucial for hippocampal function, thereby supporting this kinase as a relevant target for the treatment of AD.
In this study we used 12-month-old SAMP8 mice, an AD model, to examine the effects GSK-3β may cause regarding the cognitive impairment and oxidative stress associated with AD.
Results showed that co-administration of CA to d-gal/AlCl<sub>3</sub> induced AD-like rat models significantly increased the levels of protein phosphatase 2 (PP2A) and decreased the levels of glycogen synthase kinase-3 beta (GSK-3β).
Glycogen synthase kinase 3β (GSK-3β) is a widely investigated molecular target for numerous diseases including Alzheimer's disease, cancer, and diabetes mellitus.
Tau-Centric Multitarget Approach for Alzheimer's Disease: Development of First-in-Class Dual Glycogen Synthase Kinase 3β and Tau-Aggregation Inhibitors.
Data presented hereby will display a plethora of information as to how to interfere with progression of AD through the route of GSK-3β activity control.