title: Reversing synapse loss in Alzheimer's disease: Rho-guanosine triphosphatases and insights from other brain disorders.
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.
authors.affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, and Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, 10032, USA, rl2040@cumc.columbia.edu.
authors.forename: Roger
authors.initials: R
authors.lastname: Lefort
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology*; D000818:Animals; D001927:Brain Diseases / Q000201:enzymology / Q000473:pathology; D020690:GTPase-Activating Proteins / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000473:pathology*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D020741:rho GTP-Binding Proteins