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Cited by 68Alzheimer's disease research and treatmentsProtein Kinase Regulation and GTPase SignalingDementia and Cognitive Impairment Research

Rac1 activation links tau hyperphosphorylation and Aβ dysmetabolism in Alzheimer’s disease

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Borin, Mirta, Saraceno, Claudia, Catania, Marcella, Lorenzetto, Erika, Pontelli, Valeria, Paterlini, Anna, Fostinelli, Silvia, Avesani, Anna +8 more·2018·Acta Neuropathologica Communications
DOI 10.1186/s40478-018-0567-4PMC PMC6045891
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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 Aβ 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.

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  • Compared with non-demented controls, the level of RAC1 in the frontal cortex of AD patients is decreased, but it is transiently decreased in the brains of an animal model of AD (3xTg, 7 months).

    “Compared with that in non-demented controls, the level of RAC1 in the frontal cortex of AD patients is decreased, but it is transiently decreased in the brains of an animal model of AD (3xTg, 7 months)150.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [150]

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Authors
Borin, M., Saraceno, C., Catania, M., Lorenzetto, E., Pontelli, V., Paterlini, A., Fostinelli, S., Avesani, A., Di Fede, G., Zanusso, G., Benussi, L., Binetti, G., Zorzan, S., Ghidoni, R., Buffelli, M., & Bolognin, S.
Affiliations
  • University of Verona (IT)
  • Centro San Giovanni di Dio Fatebenefratelli (IT)
  • Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
  • Luxembourg Institute of Science and Technology (LU)
  • University of Luxembourg (LU)
Corresponding author
Bolognin, Silvia
ORCID
Venue
Acta Neuropathologica Communications
Publisher
Springer Science and Business Media LLC
Published
2018-07-13
Volume
6
Issue
1
Pages
61-61
ISSN
2051-5960 (ISSN-L)
DOI
10.1186/s40478-018-0567-4
PMC
PMC6045891
OpenAlex
W2884780489
Cited by
68
References
4
Citations by year
2026: 5 · 2025: 7 · 2024: 8 · 2023: 11 · 2022: 11 · 2021: 10 · 2020: 13 · 2019: 3
FWCI
4.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Ministero della Salute (n.173/GR-2011-02348526)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Rac1, Alzheimer's disease, tau hyperphosphorylation, Rho GTPases, dendritic spine loss, APP processing, 3xTg-AD mice, actin cytoskeleton, therapeutic target
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Animals, Cells, Cultured, Cognition Disorders, Disease Models, Animal, Embryo, Mammalian, Fatty Acids, Unsaturated, Gene Expression Regulation, Humans, Mice, Inbred C57BL, Mice, Transgenic, Neuroblastoma, Neurons, Phosphorylation, Amyloid beta-Peptides, tau Proteins, rac1 GTP-Binding Protein, Dendritic Spines, Mice, Presenilin-1

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