Deletion of Small GTPase H-Ras Rescues Memory Deficits and Reduces Amyloid Plaque-Associated Dendritic Spine Loss in Transgenic Alzheimer's Mice.

Alzheimer's disease (AD) is a fatal neurodegenerative disorder, affecting millions of lives without a cure. While the molecular mechanism of AD remains obscure, emerging evidence suggests that small GTPases, a group of GTP-binding proteins that regulate a plethora of essential cellular events, modulate the pathogenic process of AD. Among those, the small GTPase H-Ras, extensively studied in cancer, regulates synaptic function, and both upstream and downstream signaling pathways of H-Ras have been implicated in AD. However, the role of H-Ras per se in AD pathogenesis had not been explored previously. In the present study, the impact of Hras deletion on cognitive function and amyloid pathology was investigated in transgenic APP/PS1 mice of AD. Behavioral assessments showed that the absence of Hras rescued spatial memory deficit in APP/PS1 mice at 9 months of age. The pathological evaluation demonstrated that Hras deletion reduced cortical amyloid deposition and astrogliosis. Furthermore, Hras deficiency protected against amyloid plaque-associated loss of dendritic spines in APP/PS1 mice. Intriguingly, canonical signaling pathways downstream of H-Ras were not affected by the absence of Hras in the brain. Unbiased transcriptomic analysis revealed that lack of H-Ras affected the expression of select genes in the brain of AD mice and identified a novel connection between H-Ras and Annexin A4, a calcium-dependent phospholipid-binding protein that has been shown to regulate membrane repair, neuroinflammation, and calcium homeostasis. Taken together, these data indicate that H-Ras modifies the pathogenic process of AD and may serve as a potential therapeutic target for AD.

Optic nerve as a source of activated retinal microglia post-injury.

Using mice expressing green fluorescent protein (GFP) from a transgenic CD11c promoter we found that a controlled optic nerve crush (ONC) injury attracted GFPhi retinal myeloid cells to the dying retinal ganglion cells and their axons. However, the origin of these retinal myeloid cells was uncertain. In this study we use transgenic mice in conjunction with ONC, partial and full optic nerve transection (ONT), and parabiosis to determine the origin of injury induced retinal myeloid cells. Analysis of parabiotic mice and fate mapping showed that responding retinal myeloid cells were not derived from circulating macrophages and that GFPhi myeloid cells could be derived from GFPlo microglia. Comparison of optic nerve to retina following an ONC showed a much greater concentration of GFPhi cells and GFPlo microglia in the optic nerve. Optic nerve injury also induced Ki67+ cells in the optic nerve but not in the retina. Comparison of the retinal myeloid cell response after full versus partial ONT revealed fewer GFPhi cells and GFPlo microglia in the retina following a full ONT despite it being a more severe injury, suggesting that full transection of the optic nerve can block the migration of responding myeloid cells to the retina. Our results suggest that the optic nerve can be a reservoir for activated microglia and other retinal myeloid cells in the retina following optic nerve injury.

Systemic or Forebrain Neuron-Specific Deficiency of Geranylgeranyltransferase-1 Impairs Synaptic Plasticity and Reduces Dendritic Spine Density.

Isoprenoids and prenylated proteins regulate a variety of cellular functions, including neurite growth and synaptic plasticity. Importantly, they are implicated in the pathogenesis of several diseases, including Alzheimer's disease (AD). Recently, we have shown that two protein prenyltransferases, farnesyltransferase (FT) and geranylgeranyltransferase-1 (GGT), have differential effects in a mouse model of AD. Haplodeficiency of either FT or GGT attenuates amyloid-ß deposition and neuroinflammation but only reduction in FT rescues cognitive function. The current study aimed to elucidate the potential mechanisms that may account for the lack of cognitive benefit in GGT-haplodeficient mice, despite attenuated neuropathology. The results showed that the magnitude of long-term potentiation (LTP) was markedly suppressed in hippocampal slices from GGT-haplodeficient mice. Consistent with the synaptic dysfunction, there was a significant decrease in cortical spine density and cognitive function in GGT-haplodeficient mice. To further study the neuron-specific effects of GGT deficiency, we generated conditional forebrain neuron-specific GGT-knockout (GGTf/fCre+) mice using a Cre/LoxP system under the CAMKIIα promoter. We found that both the magnitude of hippocampal LTP and the dendritic spine density of cortical neurons were decreased in GGTf/fCre+ mice compared with GGTf/fCre- mice. Immunoblot analyses of cerebral lysate showed a significant reduction in cell membrane-associated (geranylgeranylated) Rac1 and RhoA but not (farnesylated) H-Ras, in GGTf/fCre+ mice, suggesting that insufficient geranylgeranylation of the Rho family of small GTPases may underlie the detrimental effects of GGT deficiency. These findings reinforce the critical role of GGT in maintaining spine structure and synaptic/cognitive function in development and in the mature brain.