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 RhoGTPase 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 GTPaseactivating proteins. Several of these have been linked to various aspects of AD, and each offers a novel potential therapeutic target for AD.

Reducing expression of synapse-restricting protein Ephexin5 ameliorates Alzheimer’s-like impairment in mice

“…Previous studies have suggested the importance of RhoA GEFs in the progression of AD and as potential drug targets to treat AD (25). We believe that our study is one of the few to test this hypothesis and, further, to identify a RhoA GEF, Ephexin5, as being relevant to AD-associated dendritic spine degeneration and cognitive dysfunction.…”

Rho GTPases as therapeutic targets in Alzheimer’s disease

“…Due to the crosstalk and dysregulation of Rho GTPases, it would also be necessary to determine the role of Rho GTPase regulators (GEFs, GAPS, and GDIs) in AD. Indeed, Rho GTPase regulators and effectors have been implicated in AD (reviewed in [ 2 , 12 ]). We have recently reviewed the activation of Cdc42 in Ras-related cancers as well as the effectors and regulators [ 31 ] given that oncogenic pathways are also activated in AD [ 3 ].…”

“…Rho GTPases play critical roles in dendritic spine morphogenesis and synaptic plasticity [ 10 , 11 ]. Aberrant activity of the Rho GTPases, their regulators (GEFs, GAPS, and GDIs), and effectors in AD has been reviewed [ 2 , 12 ]. However, the therapeutic potential of Rho GTPases in AD remains unclear.…”

Rate of brain aging and APOE ε4 are synergistic risk factors for Alzheimer’s disease

“…More specific pathway categories for down-regulated genes include “glutamate signaling,” “dopamine feedback in cAMP signaling” (not shown, P = 1 × 10 −5 ), and “rho GTPases” (Fig 4A). The rho-GTPases are particularly interesting because they are known regulators of synaptic spine formation and actin cytoskeletal dynamics (Morrison & Baxter, 2012; Lefort, 2015). Thus, these changes are consistent with earlier findings showing deficits in synaptic function and neuronal signaling.…”

“…Our analysis also provides several molecular insights into brain aging in the neurologic disease-free cohorts. First, aging is associated with changes in transcripts affecting rho-GTPases, which are associated with synapse formation and actin cytoskeleton dynamics in axons (Lefort, 2015). Other top categories of transcripts reduced in the aging brain encode GTPase inhibitors and other synaptic function-related proteins.…”