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

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-beta 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 platelet-derived growth factor subunit B (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, Abeta 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.