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-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.
Subject(s)
Alzheimer Disease/genetics , Amyloid beta-Protein Precursor/genetics , Brain/pathology , Myelin Proteins/deficiency , Alzheimer Disease/pathology , Alzheimer Disease/prevention & control , Amyloid beta-Protein Precursor/physiology , Amyloid beta-Protein Precursor/toxicity , Animals , Crosses, Genetic , Dentate Gyrus/chemistry , Dentate Gyrus/pathology , Disease Models, Animal , Disease Progression , Frontal Lobe/pathology , Gliosis/etiology , Gliosis/pathology , Humans , Maze Learning , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Mice, Knockout , Mice, Transgenic , Myelin Proteins/genetics , Myelin Proteins/physiology , Nerve Tissue Proteins/analysis , Neurites/ultrastructure , Nogo Proteins , Plaque, Amyloid/pathology , Point Mutation , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/toxicity , Species SpecificityABSTRACT
OBJECTIVE: To test whether progesterone or progesterone receptors are important mediators of premenstrual syndrome (PMS) and whether progesterone antagonist RU 486 would alleviate symptoms. METHODS: Following extensive screening including physical and psychological assessment, seven women with severe PMS participated in a 6-month, randomized, double-blind, placebo-controlled, crossover study. The treatment included 3 months of low-dose RU 486 (5 mg alternate days for four doses, beginning 3 days after the urinary LH surge) or placebo, administered in a similar fashion. Symptoms were evaluated using the Calendar of Premenstrual Experiences, Beck Depression Inventory, State-Trait Anxiety Inventory, and the Profile of Mood States. RESULTS: Symptoms of PMS were similar during RU 486 and placebo treatments. CONCLUSION: Luteal-phase administration of low-dose RU 486 does not significantly reduce the physical or behavioral manifestations of PMS.
