GSK3β and Tau Protein in Alzheimer's Disease and Epilepsy

Abstract

Alzheimer's disease (AD) is the most common form of dementia present in older adults; its etiology involves genetic and environmental factors. In recent years, epidemiological studies have shown a correlation between AD and chronic epilepsy since a considerable number of patients with AD may present seizures later on. Although the pathophysiology of seizures in AD is not completely understood, it could represent the result of several molecular mechanisms linked to amyloid beta-peptide (Aβ) accumulation and the hyperphosphorylation of tau protein, which may induce an imbalance in the release and recapture of excitatory and inhibitory neurotransmitters, structural alterations of the neuronal cytoskeleton, synaptic loss, and neuroinflammation. These changes could favor the recurrent development of hypersynchronous discharges and epileptogenesis, which, in a chronic state, favor the neurodegenerative process and influence the cognitive decline observed in AD. Supporting this correlation, histopathological studies in the brain tissue of temporal lobe epilepsy (TLE) patients have revealed the presence of Aβ deposits and the accumulation of tau protein in the neurofibrillary tangles (NFTs), accompanied by an increase of glycogen synthase kinase-3 beta (GSK3β) activity that may lead to an imminent alteration in posttranslational modifications of some microtubule-associated proteins (MAPs), mainly tau. The present review is focused on understanding the pathological aspects of GSK3β and tau in the development of TLE and AD.

Keywords: GSK3β; epilepsy; hippocampal sclerosis; neurodegeneration; tau protein.

Figure 1

Tau protein. (A) Tau gene. Exons 2, 3, and 10 are alternatively spliced in the central nervous system (CNS). Exons 9–12 each contain the microtubule-binding domain (MBD). Exons 4a and 6 have been expressed in isoforms of the peripheral nervous system, whereas exon 8 has not been reported in any isoform. (B) Different isoforms of tau protein are expressed in the CNS. The expression of different isoforms is regulated by development. Isoforms with three repeated domains are expressed preferentially in fetal stages, whereas in the adult stages they are characterized by the presence of the six isoforms. The repeated domains that bind to microtubules (MTs) are designated as R1, R2, R3, and R4. Another characteristic is the presence or absence (0N) of one (1N) or two (2N) inserts located in the amino terminus of the protein.

Figure 2

Putative phosphorylation sites on tau protein. The native tau protein is phosphorylated in serine or threonine residues and contains 85 putative phosphorylation sites. Several amino acids are phosphorylated in Alzheimer’s disease (AD) brain (red boxes) and both normal and AD brains (green boxes). The localization of antibody epitopes is indicated (purple circles).

Figure 3

Glycogen synthase kinase-3 beta (GSK3β and epilepsy. Impaired PI3K/Akt and Wnt/b-catenin signaling pathways can induce GSK3β increased activity, which could promote N-methyl-D-aspartate receptor (NMDAR) overstimulation, leading to hyperexcitability and synaptic plasticity alterations. Probably, this mechanism represents the major link between GSK3β and seizures in the hippocampus, although some studies have proposed that GSK3β increased activity confers protection. In another way, GSK3β could favor tau hyperphosphorylation, promoting axonal transport impairment and hippocampal neuronal death. Hyperphosphorylated tau actively participates in hyperexcitability and neurodegeneration. GSK3β also promotes a mitochondrial pro-apoptotic profile (high BAX/Bcl2 ratio). In this sense, GSK3β also could trigger dysfunctional neurogenesis, which prevents recovery of the synaptic equilibrium of the hippocampus, one neurogenic structure.

Figure 4

Schematic representation of the roles of tau and GSK3β in the neurodegeneration process. The tau protein can be hyperphosphorylated by an increase in GSK3β activity. pTau loses its union to the MTs, favoring its aggregation and the formation of neurofibrillary tangles (NFTs). These aggregates, like neuritic plaques (NPs), promote an imbalance of hippocampal neuronal networks and synaptic dysfunction, which in turn may favor neuronal death through apoptosis or necrosis. Finally, these alterations lead to processes of hyperexcitability and excitotoxicity in the hippocampus, favoring increased seizure susceptibility.