Glycogen Synthase Kinase-3 Modulation in Neurodegenerative Diseases

Glycogen synthase kinase-3 (GSK-3) is a constitutively active serine/threonine kinase with two isoforms, GSK-3α and GSK-3β, that occupies a central role in neuronal signalling, metabolism and survival. In neurodegenerative diseases such as Alzheimer’s and related tauopathies, aberrant activation of GSK-3 drives hyperphosphorylation of tau, promotes amyloid-β production and perturbs autophagy, synaptic plasticity and mitochondrial function. Modulation of GSK-3 activity—through small-molecule inhibitors, gene silencing or indirect regulation via upstream pathways—has thus emerged as a promising strategy to restore proteostasis, suppress neuroinflammation and improve cognitive outcomes. Recent advances have further elucidated the bidirectional interplay between GSK-3 and key metabolic regulators, highlighting opportunities to target age-associated decline in neuronal energy homeostasis alongside classical proteinopathy hallmarks. Overall, fine-tuned inhibition or redirection of GSK-3 offers a multifaceted approach to slow or halt progressive neurodegeneration.

Research from Nature Portfolio

Recent studies have uncovered a neuron-specific isoform of the metabolic coactivator PGC-1α whose expression is repressed with age and is regulated downstream of GSK-3β. Functional analyses in murine cortical tissue reveal that modulation of GSK-3β activity restores PGC-1α-driven programmes of mitochondrial biogenesis and suppresses ageing signatures in neurons. In parallel, seminal reviews on tau phosphorylation have mapped the structural landscape of GSK-3β’s ATP-binding pocket and explored both ATP-competitive and allosteric inhibitor designs. These analyses emphasise the feasibility of developing compounds with high selectivity for GSK-3β that penetrate the central nervous system, modulate tau phosphorylation in transgenic models and minimise off-target effects on normal kinase functions.

Glycogen Synthase Kinase-3 Modulation in Neurodegenerative Diseases publication trend

The graph below shows the total number of articles in glycogen synthase kinase-3 modulation in neurodegenerative diseases across all publications each year (not limited to Nature Index journals).

Technical terms

GSK-3: A constitutively active serine/threonine kinase with two isoforms (α and β) involved in numerous signalling pathways. Tau hyperphosphorylation: Excessive addition of phosphate groups to tau protein, leading to microtubule destabilisation and neurofibrillary tangle formation. Amyloid-β (Aβ): Peptides derived from amyloid precursor protein that aggregate into plaques in Alzheimer’s disease. PGC-1α: A transcriptional coactivator that regulates mitochondrial biogenesis and oxidative metabolism. siRNA: Small interfering RNA molecules used to silence specific gene expression by promoting mRNA degradation. Multivesicular bodies (MVBs): Endosomal structures involved in sorting of membrane proteins for degradation or exocytosis.

References

1. Neuron-specific isoform of PGC-1α regulates neuronal metabolism and brain aging. Nature Communications (2025).
2. Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases. Nature Reviews Drug Discovery (2007).
3. Identification of AS1842856 as a novel small‐molecule GSK3α/β inhibitor against Tauopathy by accelerating GSK3α/β exocytosis. Aging Cell (2024).
4. Systemic Treatment with siRNA Targeting Gamma-Secretase Activating Protein Inhibits Amyloid-β Accumulation in Alzheimer’s Disease. Biomaterials Research (2024).
5. GSK-3 and Tau: A Key Duet in Alzheimer’s Disease. Cells (2021).