Targeting GSK3 signaling as a potential therapy of neurodegenerative diseases and aging

ABSTRACT

Introduction: Glycogen synthase kinase 3 (GSK3) is at the center of cellular signaling and controls various aspects of brain functions, including development of the nervous system, neuronal plasticity and onset of neurodegenerative disorders.

Areas covered: In this review, recent efforts in elucidating the roles of GSK3 in neuronal plasticity and development of brain pathologies; Alzheimer’s and Parkinson’s disease, schizophrenia, and age-related neurodegeneration are described. The effect of microglia and astrocytes on development of the pathological states is also discussed.

Expert opinion: GSK3β and its signaling pathway partners hold great promise as therapeutic target(s) for a multitude of neurological disorders. Activity of the kinase is often elevated in brain disorders. However, due to the wide range of GSK3 cellular targets, global inhibition of the kinase leads to severe side-effects and GSK3 inhibitors rarely reach Phase-2 clinical trials. Thus, a selective modulation of a specific cellular pool of GSK3 or specific down- or upstream partners of the kinase might provide more efficient anti-neurodegenerative therapies.

KEYWORDS:

• Synaptic plasticity
• brain aging
• inflammation
• Alzheimer’s disease
• Parkinson’s disease
• schizophrenia
• astrocytes

Article highlights

• Glycogen synthase kinase 3 (GSK3) controlling nervous system development, signal transmission and memory formation lies at focal point of cellular signaling in brain

• GSK3 is deregulated in numerous neurodegenerative and psychiatric disorders which makes it a promising therapeutic target

• Due to the wide range of GSK3 cellular targets, global inhibition of the kinase leads to severe side effects and GSK3 inhibitors rarely reach phase-2 clinical trials.

• Recent efforts in elucidating the roles of GSK3 in neuronal plasticity, development of brain pathologies and age-related neurodegeneration are described.

• The necessity for selective modulators of a specific cellular pool of GSK3 or specific down- or upstream partners of the kinase is highlighted.

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Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the Polish Ministry of Science and Higher Education [grant number UMO-2015/19/B/NZ1/00332 to AG and DR] and the East Carolina University Grants [grant number 111104 to JAM], [grant number 111110-668715-0000 to JAM].