Pyruvate kinase M2 in Alzheimer's disease: from dysregulation to therapeutic inhibition
Esmaeel G Gojani1, Robert J Sutherland1, Majid H Mohajerani1,2
1Department of Neuroscience, Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge, AB, Canada T1K 3M4.
Abstract:
Pyruvate kinase M2 (PKM2) has emerged as a critical regulator of Alzheimer's disease pathophysiology. This review synthesizes current evidence demonstrating how PKM2 dysregulation contributes to cognitive decline by driving Warburg-like metabolic reprogramming, altering post-translational modifications and modulating protein-protein interactions. These processes collectively impair cell-cycle control, transcriptional regulation and cytoskeletal stability in neuronal cells. We further examine the impact of PKM2 on neuroinflammation, highlighting its context-dependent roles in microglia and astrocytes. In addition, we provide a comprehensive evaluation of natural and synthetic PKM2 modulators with therapeutic potential in Alzheimer's disease, summarizing their mechanisms and reported outcomes. Clarifying the molecular basis of PKM2-mediated neurodegeneration and rigorously testing these modulators in preclinical models will be essential steps towards developing PKM2-targeted strategies for Alzheimer's disease intervention.
Insights
Pyruvate kinase M2 (PKM2) dysregulation drives Alzheimer's disease by altering cell metabolism and function. Targeting PKM2 offers a promising therapeutic strategy for neurodegenerative disease intervention.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Pyruvate kinase M2 (PKM2) is increasingly recognized for its role in Alzheimer's disease (AD) pathogenesis.
- PKM2 dysregulation contributes to cognitive decline and neurodegeneration in AD.
Purpose of the Study:
- To review the multifaceted roles of PKM2 in AD.
- To explore PKM2's impact on cellular metabolism, protein modifications, and neuroinflammation.
- To evaluate potential PKM2-targeting therapeutics for AD.
Main Methods:
- Literature review synthesizing current evidence on PKM2 in AD.
- Analysis of PKM2's influence on metabolic reprogramming (Warburg-like effect).
- Examination of PKM2's effects on post-translational modifications and protein interactions.
Main Results:
- PKM2 dysregulation impairs neuronal cell-cycle control, transcription, and cytoskeletal stability.
- PKM2 exhibits context-dependent roles in microglia and astrocytes, influencing neuroinflammation.
- Various natural and synthetic PKM2 modulators show therapeutic potential for AD.
Conclusions:
- Understanding PKM2's molecular mechanisms in neurodegeneration is crucial for AD intervention.
- Further preclinical testing of PKM2 modulators is necessary to develop effective AD therapies.
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