GSK-3 and Tau: A Key Duet in Alzheimer's Disease

Abstract

Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine kinase with a plethora of substrates. As a modulator of several cellular processes, GSK-3 has a central position in cell metabolism and signaling, with important roles both in physiological and pathological conditions. GSK-3 has been associated with a number of human disorders, such as neurodegenerative diseases including Alzheimer's disease (AD). GSK-3 contributes to the hyperphosphorylation of tau protein, the main component of neurofibrillary tangles (NFTs), one of the hallmarks of AD. GSK-3 is further involved in the regulation of different neuronal processes that are dysregulated during AD pathogenesis, such as the generation of amyloid-β (Aβ) peptide or Aβ-induced cell death, axonal transport, cholinergic function, and adult neurogenesis or synaptic function. In this review, we will summarize recent data about GSK-3 involvement in these processes contributing to AD pathology, mostly focusing on the crucial interplay between GSK-3 and tau protein. We further discuss the current development of potential AD therapies targeting GSK-3 or GSK-3-phosphorylated tau.

Keywords: Alzheimer’s disease; GSK-3; neurodegeneration; tau phosphorylation.

Figure 1

Overexpression of GSK-3β induces tau-dependent AD-like pathology. Transgenic mice overexpressing GSK-3β (Tet/GSK-3β mice) in forebrain show tau hyperphosphorylation and relocalization to the somatodendritic compartment in hippocampal neurons, in correlation with different signs of neurodegeneration. These mice recapitulate different aspects of AD pathology, which—at least partially—rely on GSK-3β-induced hyperphosphorylation of tau protein. A similar role for GSK-3α in tau hyperphosphorylation found in AD cannot be precluded, as it has not been extensively analyzed. Abbrev: AHN: Adult hippocampal neurogenesis.

Figure 2

Tau functional domains and phosphorylation sites. Schematic illustration of tau functional domains and localization of the best characterized phosphorylation sites. GSK-3 phosphorylation sites are highlighted in fuchsia. The scheme illustrates the longest tau isoform (tau4R, 441aa). The N-terminal projection domain (aa1-165) contains two inserts, N1 (aa46-75) and N2 (aa76-102). The proline-rich region (PRR) (aa165-242) contains numerous phosphorylation sites, for GSK-3 and other kinases. Tau binds to MTs through the microtubule-binding region (MTBR), which comprises 4 imperfect repeats: R1 (aa243-273), R2 (aa274-304). R3 (aa305-335) and R4 (aa336-367). The C-terminal domain is formed by aa368-441.

Figure 3

Alterations to dendritic tree morphology and postsynaptic densities in newborn granule neurons upon GSK-3β overexpression or exposure to soluble tau. Under physiological situations (control), maturation of newborn granule hippocampal neurons leads to a dendritic tree with a “Y-shape” that presents a single apical primary dendrite and several distal branches. Upon GSK-3β overexpression (OE) or soluble tau exposure, cells acquire a “V-shape”, with numerous apical dendrites and atrophied distal branching, and show a marked depletion of postsynaptic densities (•PSDs). Neurons from AD patients show similar morphological alterations. At least part of the observed effects of GSK-3β in AHN might be mediated by tau protein.

Figure 4

Interplay between GSK-3α and tau during NMDAR-mediated LTD. Tau is required for the transient anchoring of GSK-3α at dendritic spines, a key process during NMDAR-mediated LTD. On the other hand, GSK-3-mediated phosphorylation of tau in Ser 396 is necessary for LTD. Tau contributes further to other crucial aspects of LTD, such as the internalization of AMPAR and NMDAR extrasynaptic currents. It is still controversial whether tau is upstream and/or downstream of GSK-3α in LTD.