Herein, we highlight nine major targets associated with AD, which are acetylcholine esterase (AChE), beta-site amyloid precursor protein cleaving enzyme 1 (β-secretase, BACE-1), glycogen synthase kinase 3 beta (GSK-3β), monoamine oxidases (MAOs), metal ions in the brain, N-methyl-D-aspartate (NMDA) receptor, 5-hydroxytryptamine (5-HT) receptors, the third subtype of histamine receptor (H<sub>3</sub> receptor), and phosphodiesterases (PDEs), and their respective relationship to the disease network.
This work aims to provide a novel tool for early diagnosis and pathological mechanism exploration about AD by detecting inchoate change of GSK-3β content in body fluid, thus to precaution the risk of Alzheimer's disease.
The association between single nucleotide polymorphisms of GSK 3β gene and sporadic Alzheimer's disease in a cohort of southern Chinese Han population.
The minor allele (T) of the promoter rs334558 within GSK3B was associated with an increased risk of LOAD (odds ratios/OR=1.381, P=0.006), T carriers may be easier to develop AD (P=0.002, power=0.92).
In this study, we investigated the associations between single-nucleotide polymorphisms in GAB2 (rs2373115), GSK3B (rs6438552) and SORL1 (rs641120) and Alzheimer's disease (AD), both alone and in combination with the APOE*4 allele.
Stereoisomers of Schisandrin B Are Potent ATP Competitive GSK-3β Inhibitors with Neuroprotective Effects against Alzheimer's Disease: Stereochemistry and Biological Activity.
Main genes involved in AD include mutational loci (APP, PS1, PS2, TAU) and multiple susceptibility loci (APOE, A2M, AACT, LRP1, IL1A, TNF, ACE, BACE, BCHE, CST3, MTHFR, GSK3B, NOS) distributed across the human genome.
Consistent interaction between GSK3B and MAPT genes in three late-onset AD cohorts was observed, with the GSK3B haplotype (T-T) significantly increasing the risk for AD in individuals with at least one H2 haplotype (odds ratio, 1.68-2.33; p = 0.005-0.036).
However, little is known about the potential role of the GSK-3βrs334558 polymorphism, which has been associated with amnestic mild cognitive impairment (aMCI), which is itself associated with a high risk of AD.
Sarkosyl-insoluble fractions of the hippocampus were enriched in p38-P and GSK-3 beta-P in Alzheimer's disease (AD) cases, processed in parallel for comparative purposes, but not in the P310L mutation.
Twelve GSK3B tag single-nucleotide polymorphisms (SNPs), together with the previously AD-associated rs334558, were analyzed in 583 AD patients and 673 controls.
The TDB (located within the AIS) was impaired when AIS components (ankyrin G, EB1) were knocked down or when glycogen synthase kinase-3β (GSK3β; an AD-associated kinase tethered to the AIS) was overexpressed.
Previous studies in high-fat diet-induced AD animal models have shown that brain insulin resistance in these animals leads to the accumulation of amyloid beta (Aβ) and the reduction in GSK-3β phosphorylation, which promotes tau phosphorylation to cause AD.
Glycogen synthase kinase-3β (GSK-3β), a serine/threonine kinase also known as tau protein kinase I, has been implicated in the pathogenic conditions of Alzheimer's disease.
In experiments with cultured HEK293T cells, we show here that GSK3β stabilizes synaptic acetylcholinesterase (AChE-S), a critical component of AD development.
The prolyl isomerase Pin1 and glycogen synthase kinase-3β (GSK3β) have been shown to have the opposite effects on APP processing and Tau hyperphosphorylation, relevant to the pathogenesis of AD.
A physicochemical descriptor based method for effective and rapid screening of dual inhibitors against BACE-1 and GSK-3β as targets for Alzheimer's disease.
For this reason, other biochemical pathways associated with the pathophysiology of AD have been explored as alternatives to the treatment of this condition such as inhibition of β-secretase and glycogen synthase kinase-3β.
Thus, our previous and present findings raise the unifying prospect that Aβ•CaSR signaling plays a crucial role in AD development and progression by simultaneously activating (i) the amyloidogenic processing of amyloid precursor holoprotein, whose upshot is a surplus production and secretion of Aβ<sub>42</sub> oligomers, and (ii) the GSK-3β-mediated increased production of p-Tau oligomers which are next released extracellularly inside exosomes.
In this sense, here we report the rational design of a multi-target directed ligand (MTDL) for AD based on virtual screening and bioinformatic analyses, exploring the molecular targets β-secretase (BACE-1), glycogen synthase kinase-3β (GSK-3β) and acetylcholinesterase (AChE).