P2-001

S232

Poster P2:: Monday Posters

Results (OC) indicate that memantine had a significant effect over placebo upon symptoms in the Mood cluster at both weeks 12 (P⫽.034) and 24 (P⫽.033), with 65.5% of patients in the memantine group showing a positive response at week 24. Memantine also had a significant effect over placebo (OC) upon symptoms of Psychosis at both weeks 12 (P⫽.006) and 24 (P⬍.001), with 80.7% of patients in the memantine group showing a positive response in this domain at week 24. The response difference (OC) between memantine and placebo patients at week 24 was 12.2% and 18.9% for Mood and Psychosis clusters, respectively. LOCF analysis yielded comparable results. Effects of memantine on Frontal symptoms were not significant, while the effects on Other symptoms were significant at week 24 using LOCF analysis (P⫽.037), but not OC analysis (P⫽.058). Conclusions: Taken together, these results suggest that memantine provides specific behavioral benefits for mood and psychosis-related symptoms associated with AD. MONDAY, JULY 17, 2006 POSTER PRESENTATIONS P2 P2-001

PATHOMORPHOLOGICAL CORRELATES OF BEHAVIORAL ABNORMALITIES IN AMYLOID INJECTION RODENT MODEL OF ALZHEIMER’SLIKE PATHOLOGY

Mikhail Stepanichev1, Yulia Moiseeva1, Natalia Lazareva1, Danil Peregud2, Mikhail Onufriev1, Natalia Gulyaeva1, 1Institute of Higher Nervous Activity and Neurophysiology, Moscow, Russian Federation; 2National Research Center on Addictions, Moscow, Russian Federation. Contact e-mail: [email protected] Background: Intracerebroventricular administration of amyloid-␤ (A␤) peptide (25-35) to rats induces Alzheimer’s-like memory disturbances, in particular, impairments of spatial and non-spatial working memory, as well as changes in emotional status. Objective(s): The aim of the present work was to investigate morphological changes underlying these behavioral impairments. Methods: A␤(25-35) was injected into male Wistar rats intracerebroventricularly, bilaterally, at a dose of 15 nmol. The rats were tested in a series of behavioral tasks including spontaneous alternation, social recognition, radial maze, plus-maze, and forced swim test. After behavioral testing histological and immunohistochemical studies were performed. Results: Working memory abnormalities appeared as early as two weeks after surgery and were evident at least until six months. However, the first signs of neuronal death were not revealed earlier than one month after A␤(25-35) administration, though significant neurodegenerative changes in the hippocampus and neocortex could be demonstrated three and six months after surgery. The regions of the most prominent neuronal cell loss were hippocampal CA1 field, frontal and fronto-parietal cortex. The number of live neurons in the CA1 hippocampal field negatively correlated with the number of reference and working memory errors in a radial maze. In this animal model, cognitive impairments usually precede neurodegenerative changes. This may be due not only to the putative effects of A␤ on cholinergic transmission but also on the neurogenesis process, which may be related to both learning and brain repair. We have demonstrated that A␤(25-35) inhibits neuronal proliferation in the dentate gyrus during the first two weeks after the peptide administration. Since A␤(25-35) activates neuronal NO-synthase concurrently, we suggest that A␤-induced increase in NO production may underlie decreased neurogenesis in rat hippocampus. Conclusions: The data presented show that central administration of A␤(25-35) to rats may be used to model relevant mechanisms of Alzheimer’s-like pathology. The study is supported by RFBR grant.

P2-002

LEVELS AND TURNOVER OF ENDOGENOUS APP METABOLITES IN THE WILD-TYPE MOUSE BRAIN

Matthew J. Mazzella, Nichole S. Diaz, Jason Berger, Paul M. Mathews, Nathan Kline Institute, Orangeburg, NY, USA. Contact e-mail: [email protected] Background: The metabolism of the amyloid precursor protein (APP) is central to the pathobiology of Alzheimer’s disease (AD), as demonstrated by the AD-causative mutations that affect APP processing, and the triplication of the App gene in Down syndrome and some cases of early-onset familial AD. While human APP transgenic models are well-studied research tools, relatively little is known about the in vivo brain metabolism of endogenous murine APP. Objective: To examine the levels and turnover of APP holoprotein, secreted APP (sAPP), APP C-terminal fragments (CTFs), and A␤ in wild-type mouse brain. Methods: The steady-state levels of APP metabolites were determined by immunoprecipitation, Western blot analysis and sandwich ELISA of mouse brain homogenates using a newly generated anti-APP/A␤ monoclonal antibody (m3.2) that recognizes with high-specificity murine APP holoprotein, A␤, sAPP␣, and ␤CTFs. The in vivo rate of brain APP metabolite turnover was estimated after treating mice with cycloheximide to inhibit protein synthesis. Results: Fractionation of membrane-associated proteins (APP holoprotein, CTFs) from soluble proteins (sAPP) demonstrated that sAPP is the most abundant APP metabolite in the mouse brain. Following cycloheximide treatment, APP holoprotein levels rapidly declined while sAPP levels remained high, suggesting that the greater levels of sAPP relative to holoprotein are due to the slower turnover of sAPP. Unexpectedly, the levels of sAPP␤ were found to be greater than those of sAPP␣. sAPP␤ was found to have a slower rate of turnover than sAPP␣, and greater levels of ␤CTFs relative to ␣CTFs were detected in the brain than have been reported in cell systems. The levels of endogenous A␤40 and A␤42 were found to decline rapidly following protein sythesis inhibition and the loss of APP holoprotein within the brain. Conclusions: The abundance and long half-life of sAPP in the brain suggest an important function(s) for this APP metabolite. The ability to examine the complex brain proteolytic processing of endogenous murine APP can be readily examined makes wild-type mice an attractive model in which to develop APP/A␤-based therapeutic strategies and to further examine the roles of various APP metabolites in normal brain function. (Supported by NINDS grants NS045357 and NS045205.) P2-003

EFFECTS OF ANTIBIOTIC TREATMENT ON CELLULAR INFLAMMATORY PROCESSES IN THE BRAIN DURING PERSISTENT CHLAMYDIA PNEUMONIAE INFECTION OF BALB/C MICE

Christine J. Hammond, C. Scott Little, Nicole Longo, Christina Procacci, Denah M. Appelt, Brian J. Balin, Philadelphia College of Osteopathic Medicine, Philadelphia, PA, USA. Contact e-mail: [email protected] Background: Neuroinflammation is a prominent contributor to pathology in sporadic late-onset Alzheimer’s Disease. Activated astrocytes and microglia, indicative of an inflammatory process, are associated with aberrant processing and deposition of amyloid in the CNS, possibly in response to a triggering agent such as Chlamydia pneumoniae. Infection with C. pneumoniae has previously been shown to initiate or exacerbate inflammatory processes (Little et al 2004). Objective: Using a mouse model, we are investigating whether treatment with moxifloxacin hydrochloride, an antibiotic effective against C. pneumoniae, has an effect on the inflammatory process and amyloid deposition in the brain induced by C. pneumoniae infection. Methods: We established a persistent infection via intranasal inoculation of young (3 months) BALB/c mice with a respiratory strain (AR-39) of C. pneumoniae. Mice were treated with antibiotic by oral gavage at 7-21 days or 56-70 days post-infection, and sacrificed at 3 and 6