# Pyruvate kinase M2 in Alzheimer’s disease: from dysregulation to therapeutic inhibition

## TL;DR

This review explores how the enzyme PKM2 contributes to Alzheimer’s disease and suggests that targeting it could offer new treatment options.

## Contribution

The paper provides a comprehensive overview of PKM2's role in Alzheimer’s disease and evaluates potential therapeutic modulators.

## Key findings

- PKM2 dysregulation affects neuronal metabolism and contributes to cognitive decline in Alzheimer’s disease.
- PKM2 modulates neuroinflammation and influences microglia and astrocyte functions.
- Natural and synthetic PKM2 modulators show therapeutic potential in Alzheimer’s disease.

## 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.

Ghasemi et al. report in this review that the metabolic enzyme pyruvate kinase M2 influences neuronal metabolism, cell-cycle re-entry, cytoskeletal regulation, amyloid-β and tau pathology, neuroinflammation and astrocyte function in Alzheimer’s disease. They conclude that targeting pyruvate kinase M2 may provide promising therapeutic avenues for slowing neurodegeneration.

Graphical Abstract