Genetic deletion of Nogo/Rtn4 ameliorates behavioral and neuropathological outcomes in amyloid precursor protein transgenic mice

Abstract

The cognitive impairment in Alzheimer's disease (AD) is associated with synaptic loss, neuritic sprouting and altered neuroplasticity. Compensatory neuritic sprouting might be beneficial, while aberrant sprouting could contribute to the neurodegenerative process. Nogo (or Rtn4) is a major myelin-derived inhibitor of axonal sprouting in adult CNS. Recent evidence has implicated both the Reticulon family of proteins and a receptor for Nogo, NgR, in reducing amyloid-β production, a key step in AD pathogenesis. To test the hypothesis that Nogo, as an inhibitor of axonal sprouting, modulates disease progression in a mouse model of AD, we introduced an APP transgene (a human APP minigene carrying the Swedish and Indiana mutations under the PDGFB promoter) into a Nogo null background and characterized the behavioral and neuropathological consequences. We found that deleting Nogo ameliorates learning and memory deficits of APP transgenic mice in the Morris water maze at an early/intermediate stage of the disease. Furthermore, deleting Nogo restored the expression levels of markers for synapto-dendritic complexity and axonal sprouting including synaptophysin, MAP2, GAP43 and neurofilament that are otherwise reduced in APP transgenic mice. Other aspects of disease progression including neuronal loss, astrogliosis, microgliosis and, importantly, Aβ levels and amyloid deposits were not significantly altered by Nogo deletion. These data support the hypothesis that Nogo-mediated inhibition of neuritic sprouting contributes to the disease progression in an APP transgenic model of AD in a way that is mechanistically distinct from what has been proposed for Rtn3 or NgR.

Human mitochondrial transcriptional factor A breaks the mitochondria-mediated vicious cycle in Alzheimer’s disease

“…Among them, expression levels of 8 genes ( ATXN10 , DCC , KIF3A , MAP1B , PAK3 , PFN2 , RTN4, UCHL1 ) were also significantly decreased in AD hippocampi (GEO DataSets GSE36980)6. Downregulation of MAP1B and UCHL1 in the AD brain have been shown previously3738, and moreover, PAK33940 and RTN44142 were known to be associated with AD pathology. Taken together, the PS1 P117L AD neurons reproduce major characteristics observed in neurons in AD brain, and are useful for understanding molecular mechanisms of AD pathology in neurons.…”

Increased migration of olfactory ensheathing cells secreting the Nogo receptor ectodomain over inhibitory substrates and lesioned spinal cord

“…unpublished results). In this respect, the single genetic ablation of MAIs [75] alone or with semaphorin receptors [76] is not strong enough to support axon regrowth after SCI. In contrast, it seems that blocking the MAI receptors NgR1 and NgR3 and CSPG receptors yields better results [71].…”

Chronic cocaine administration causes extensive white matter damage in brain: Diffusion tensor imaging and immunohistochemistry studies

“…GAP-43 plays a key role in guiding the growth of axons and modulating new connections and enables neurons to sprout new terminals (Aigner et al, 1995). Recent studies demonstrated that decrease in Nogo-A resulted in an increase in axonal plasticity as determined by GAP-43 expression (Dietrich et al, 2005; Masliah et al, 2010). Increased expression of GAP-43 was also observed in the fimbria in prenatal cocaine treated animals (Clarke et al, 1996).…”

“…Cocaine administration also produces an increase in extracellular dopamine levels, and changes in WM pathology have been observed in areas away from cc (Hermida-Ameijeiras et al, 2004; Masliah et al, 2010). Oligodendrocytes express D2 and D3 receptors for dopamine, and stimulation of these receptors resulted in decreased transition of immature oligodendrocytes to mature oligodendrocytes (Bongarzone et al, 1998).…”