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Cited by 17Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchProtein Kinase Regulation and GTPase Signaling

Reversing Synapse Loss in Alzheimer's Disease: Rho-Guanosine Triphosphatases and Insights from Other Brain Disorders

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Lefort, Roger·2015·Neurotherapeutics
DOI 10.1007/s13311-014-0328-4PMC PMC4322073
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Abstract

Alzheimer's disease (AD) is a monumental public health crisis with no effective cure or treatment. To date, therapeutic strategies have focused almost exclusively on upstream signaling events in the disease, namely on β-amyloid and amyloid precursor protein processing, and have, unfortunately, yielded few, if any, promising results. An alternative approach may be to target signaling events downstream of β-amyloid and even tau. However, with so many pathways already linked to the disease, understanding which ones are "drivers" versus "passengers" in the pathogenesis of the disease remains a tremendous challenge. Given the critical roles of Rho-guanosine triphosphatases (GTPases) in regulating the actin cytoskeleton and spine dynamics, and the strong association between spine abnormalities and cognition, it is not surprising that mutations in a number of genes involved in Rho-GTPase signaling have been implicated in several brain disorders, including schizophrenia and autism. And now, there is mounting literature implicating Rho-GTPase signaling in AD pathogenesis as well. Here, I review this evidence, with a particular emphasis on the regulators of Rho-GTPase signaling, namely guanine nucleotide exchange factors and GTPase-activating proteins. Several of these have been linked to various aspects of AD, and each offers a novel potential therapeutic target for AD.

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Authors
Lefort, R.
Affiliations
Columbia University Irving Medical Center (US)
Corresponding author
Lefort, Roger
ORCID
Lefort, Roger
Venue
Neurotherapeutics
Publisher
Elsevier BV
Published
2015-01
Volume
12
Issue
1
Pages
19-28
ISSN
1878-7479 (ISSN-L)
DOI
10.1007/s13311-014-0328-4
PMC
PMC4322073
OpenAlex
W2134565622
Cited by
17
References
8
Citations by year
2026: 3 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 1 · 2019: 2 · 2017: 3 · 2016: 1
FWCI
0.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurotherapeutics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
Alzheimer's disease, synaptic loss, Rho GTPases, actin cytoskeleton, dendritic spine dynamics, guanine nucleotide exchange factor, GTPase-activating protein, amyloid-beta, tau protein, schizophrenia, autism spectrum disorder, therapeutic target
MeSH terms
Alzheimer Disease, Animals, Brain Diseases, Humans, Synapses, Signal Transduction, Guanine Nucleotide Exchange Factors, GTPase-Activating Proteins, rho GTP-Binding Proteins

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