SPATIAL AND PLANAR DYSREGULATION OF RHOGTPASES IN HUMAN AND ALZHEIMER’S DISEASE MOUSE MODEL
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Date
2023-11-27
Access
2025-12-01
Authors
Nik Akhtar, Shayan
Journal Title
Journal ISSN
Volume Title
Publisher
East Carolina University
Abstract
Rho proteins belong to the Ras superfamily of small GTPases. In humans, the Rho family of GTPases contains 20 members out of which the most studied Rho proteins are RhoA, Rac1, and Cdc42.
Rho signaling is known to regulate actin cytoskeleton dynamics in neuronal cells which are important for
growth cone dynamics, axongenesis, neuronal polarity, synaptic plasticity, and neuronal survival. Rho
GTPases are considered molecular switches due to their dual state of activation and inactivation. Briefly,
in the inactive state, the GTPase is bound to Guanosine-5’- diphosphate (GDP) and in the active state, the
GTPase is bound to Guanosine-5’-Triphosphate (GTP). The active and inactive forms of GTPase are
controlled by three main types of proteins: Guanine nucleotide exchange factors (GEF), GTPase activating proteins (GAP), and Guanine nucleotide- dissociation inhibitors (GDI). GEFs promote inactive
to active Rho GTPase. GAPs promote active to inactive Rho GTPase. The GDI does not allow the GDP
to dissociate from the GTPase resulting in an inactive form of GTPase.A vast number of studies have implicated Rho-GTPases dysregulation in promoting
neurodegenerative diseases such as Alzheimer’s disease (AD). RhoA GTPase and ROCK1, its
downstream effector protein, increased in AD brains compared to non-AD brains. In Tg2575 AD mouse
model, RhoA levels are reduced in the synaptic terminal while they were elevated in dystrophic neurites.
Treatment of cultured neurons with beta-amyloid (Aβ) increased RhoA activity which leads to dendritic
spine loss. Rac1 expression was shown to decrease in AD cortex compared to control. In 3xTg-AD mouse model, Rac1 levels were shown to be decreased by 7 months. Inhibition of Rac1 resulted in reduced
expression of Amyloid Precursor Protein (APP) via decreasing the level of APP mRNA. Cdc42 was
increased in frontal cortex in patients suffering from Frontotemporal dementia (FTLD) compared to
control. Cdc42 conditional knockout mice demonstrated impaired synaptic plasticity. Cdc42 knockout
neurons lead to abnormal axonal morphology. Aside from the studies mentioned there are numerous other
studies highlighting the importance of Rho GTPase signaling homeostasis in neurodegeneration. Despite their importance it has been a challenge to elucidate the exact nature of dysregulation of Rho GTPases in AD. This can be attributed to several factors such as the model of choice, the specific region of the brain, as well as the different states of Rho GTPases, which is the focus of this study, such as expression vs activity. We hypothesize that there are different regional expressions of Rho-GTPases
and their activation and inactivation states in the brain.In this study we have demonstrated that there is a regional and spatial dependent change in expression and activity for both RhoA and Rac/Cdc42 activity. We demonstrated that Rho GTPase
activity changes in the different subregions of the hippocampus, such as CA3, CA2, CA1 and dentate
gyrus, and cortex. We also demonstrated that there is a dynamic nuclear to cytoplasmic redistribution of
both Rho and Rac/Cdc42 proteins in a plane dependent manner. In human brain sample Rho GTPases are
also differentially expressed in the cortex and cytoplasm. Overall, we demonstrated that Rho GTPases are
differentially dysregulated in both human AD brain samples and in 3xTg-AD mouse model.Modulation of Cdc42 through small molecules such as ZCL278, ZCL279 and ZCL367 in 3xTg AD mice showed an improvement in mental status as well as burrowing behavior. ZCL278 reduced tau in
3xTg-AD mice compared to nontreated 3xTg-AD mice. Knowing the potential of small molecules to modulate protein-protein interaction, they can be potentially used to target specific regions of the brain along the rostral to caudal dimensions to perturb a unique protein-protein interaction.