S5-04-03: Treatment during the whole continuum of Alzheimer’s disease: From evidence to guidelines

Abstract

not available. S5-04-05 LESSONS TO LEARN FROM MORE NATURALISTIC STUDIES-A DEBATE Richard Gray, University of Birmingham Clinical Trials Unit, Birmingham, United Kingdom. Contact e-mail: r.gray@bham.ac.uk Abstract not available.not available. S5-04-06 DISCUSSION OF THE AD 2000 STUDY Lon Schneider, University of Southern California, Los Angeles, CA, USA. Contact e-mail: lschneid@hsc.usc.edu Abstract not available. SUNDAY, JULY 16, 2006 POSTER PRESENTATIONS P1not available. SUNDAY, JULY 16, 2006 POSTER PRESENTATIONS P1 P1-001 MEMANTINE REVERSES COGNITIVE DEFICITS IN TRANSGENIC MICE WITH BOTH PLAQUES AND TANGLES Pradeep K. Banerjee, Lauren Billings Luhrs, Frank M. LeFerla, Forest Research Institute, Jersey City, NJ, USA; University of California, Irvine, CA, USA. Contact e-mail: laferla@uci.edu Background: Alzheimer’s disease (AD) is generally believed to result from the progressive accumulation of beta amyloid plaques and neurofibrillary tangles, which may cause or occur coincident with significant neuronal loss. Memantine, an uncompetitive NMDA receptor antagonist, is widely-prescribed in humans with AD, although the effect of this drug on progressive neuropathology remains unknown. Objective(s): In this study, using a battery of cognitive tasks, the effect of memantine was tested in triple transgenic mice which harbor mutations in three genes relevant to AD pathology (PS1M146V, APPSwe and tauP301L).These mice develop both plaques and tangles in a region-specific and age-progressive manner and also exhibit learning impairment and synaptic dysfunction. Methods: Memantine (30 mg/kg/day) was administered orally via drinking water either from 2-12 months or from 9-12 months of age in “preventative” or “reversal” trials, respectively. Results: We found that in both treatment paradigms, memantine significantly prevented memory deficits in the Morris water maze, inhibitory avoidance and novel object recognition tasks compared to vehicle-treated transgenic mice. Conclusions: These findings carry two important implications. First, memantine is able to prevent the progressive decline in cognitive functioning in these mice. Second, and perhaps more importantly, memantine is able to slow or reverse established cognitive deficits in older transgenic mice, confirming memantine’s use in individuals with established AD pathology. P1-002 SYNAPTIC DEGENERATION AND MEMORY LOSS IN A MODEL OF TAUOPATHY Cathy A. Andorfer, Mei Yue, Christopher Janus, Jada Lewis, Michael Hutton, Mayo Clinic Jacksonville, Jacksonville, FL, USA. Contact e-mail: andorfer.cathy@mayo.edu Background: Alzheimer’s disease (AD) is characterized by filamentous inclusions of the microtubule associated protein tau, known as neurofibrillary tangles (NFTs) and by beta-amyloid deposits. A direct link between these pathological hallmarks and behavioral manifestations of the disease has not been established. The memory impairment in AD correlates better with the progression of tau pathology than that of amyloid pathology, however, the strongest correlate to memory impairment is loss of synapses and synaptic function. We are currently examining the connection between tau dependent cognitive dysfunction and synaptic disruption by taking advantage of a unique mouse model of conditional tau pathology, known as rTg4510. This mouse line contains the P301L tau mutation and a tet-off activator transgene that allows for suppression of mutant tau expression via doxycycline. Objectives: 1) Determine if disruptions in synapses are involved in the pathologic and memory defects that have been observed in this mouse model. 2) Determine if suppressing mutant tau expression with doxycycline treatment leads to a recovery of memory that is related to repair of pathologic changes in synapses. Method: We have examined mice at multiple ages using the Morris Water Maze to test memory deficits. Synaptic degeneration is being analyzed based on changes in preand postsynaptic markers and loss of dendritic spines. Results: rTg4510 mice develop NFTs, neuronal death and memory loss that is reversible following suppression of the mutant tau transgene. Memory loss occurs before neuronal loss and recovery of memory occurs despite significant neuronal death. Thus there is a dissociation of neuronal death from the primary mechanism of memory loss in this model. Pre-synaptic synaptophysin S94 Poster Presentations P1