AUTHOR=Hoegy Peter , Chen Yan-Hua , Lu Qun 

TITLE=The role of small GTPases in Alzheimer’s disease tau pathologies

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=Volume 19 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2025.1650400

DOI=10.3389/fncel.2025.1650400

ISSN=1662-5102

ABSTRACT=Microtubule-associated protein (MAP) tau stabilizes neuronal microtubules in axonal transport and contributes to healthy synapses. In Alzheimer’s disease (AD), tau proteins become hyperphosphorylated, reduce microtubule binding, and aggregate into paired helical filaments (PHFs) in neurofibrillary tangles (NFTs). Although the steps of this dysregulation of tau are well established, the mechanisms by which each step is regulated remain incompletely understood. Misfolded protein aggregates, such as amyloid β-peptides (Aβ), are degraded by autophagy and lysosomal pathways, in which small GTPases play essential roles. However, how tau aggregates and spreads from nerve cells and whether small GTPases similarly play pivotal roles are not as clear. Here we review the recent evidence to propose that small GTPases are important in tau protein posttranslational phosphorylation, aggregation, and clearance. As such, small GTPases may prove to be important therapeutic targets that can reduce the AD tau burden.