Rac1 activation links tau hyperphosphorylation and Aß dysmetabolism in Alzheimer's disease

Mirta Borin, Claudia Saraceno, Marcella Catania, Erika Lorenzetto, Valeria Pontelli, Anna Paterlini, Silvia Fostinelli, Anna Avesani, Giuseppe Di Fede, Gianluigi Zanusso, Luisa Benussi, Giuliano Binetti, Simone Zorzan, Roberta Ghidoni, Mario Buffelli, Silvia Bolognin

Research output: Contribution to journalArticle

Abstract

One of the earliest pathological features characterizing Alzheimer's disease (AD) is the loss of dendritic spines. Among the many factors potentially mediating this loss of neuronal connectivity, the contribution of Rho-GTPases is of particular interest. This family of proteins has been known for years as a key regulator of actin cytoskeleton remodeling. More recent insights have indicated how its complex signaling might be triggered also in pathological conditions. Here, we showed that the Rho-GTPase family member Rac1 levels decreased in the frontal cortex of AD patients compared to non-demented controls. Also, Rac1 increased in plasma samples of AD patients with Mini- Mental State Examination < 18 compared to age-matched non demented controls. The use of different constitutively active peptides allowed us to investigate in vitro Rac1 specific signaling. Its activation increased the processing of amyloid precursor protein and induced the translocation of SET from the nucleus to the cytoplasm, resulting in tau hyperphosphorylation at residue pT181. Notably, Rac1 was abnormally activated in the hippocampus of 6-week-old 3xTg-AD mice. However, the total protein levels decreased at 7-months. A rescue strategy based on the intranasal administration of Rac1 active peptide at 6.5 months prevented dendritic spine loss. This data suggests the intriguing possibility of a dual role of Rac1 according to the different stages of the pathology. In an initial stage, Rac1 deregulation might represent a triggering co-factor due to the direct effect on Aß and tau. However, at a later stage of the pathology, it might represent a potential therapeutic target due to the beneficial effect on spine dynamics.

Original languageEnglish
Article number61
JournalActa neuropathologica communications
Volume6
Issue number1
DOIs
Publication statusPublished - Feb 23 2018

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'Rac1 activation links tau hyperphosphorylation and Aß dysmetabolism in Alzheimer's disease'. Together they form a unique fingerprint.

  • Cite this

    Borin, M., Saraceno, C., Catania, M., Lorenzetto, E., Pontelli, V., Paterlini, A., Fostinelli, S., Avesani, A., Fede, G. D., Zanusso, G., Benussi, L., Binetti, G., Zorzan, S., Ghidoni, R., Buffelli, M., & Bolognin, S. (2018). Rac1 activation links tau hyperphosphorylation and Aß dysmetabolism in Alzheimer's disease. Acta neuropathologica communications, 6(1), [61]. https://doi.org/10.1186/s40478-018-0567-4