P.4.012 Effect of memantine on levels of the amyloid beta peptide in cell cultures

I?4. Degenerative

and

vitro effects coincide with in vivo examined galautamiue-induced chauges in the GI-tract of the treated rats by their character cau be considered as maiu reason for their development.

mP4

011

Dependence in Alzheimer’s and socio-economic relevant

A. Dresse’ , B. Rive2. Pharmacology, Liege,

aud

disease is a clinical outcome

‘University of Liege, Department Belgium; ‘Altipharm, Paris, France

of

Background: Dementia patients undergo cognitive, behavioural aud fuuctioual disabilities. Patient evaluatiou is mainly based 011 disease aud severity, usually assessed using the Miui Meutal State Examination (JvIMSE). However, this scale is uot sensitive or relevant in very mild aud severe patients (1). Objective: To find a uew method of dementia patient classificatiou based 011 their disabilities by using a basic aud au iustrumeutal Activities of Daily Living (ADL) scale measured simultaneously. Method: Using the National Dementia Economic Study (NADES), a Belgian cohort of patients, fuuctioual disability was assessed using the Katz aud Lawtou Iustrumeutal Activities of Daily Living (IADL) scales. A k-meaus derived clustering method allocated patients to disability clusters according to their Katz aud Lawtou scores. In order to validate the classification, we compared socio-demographic, clinical aud costs parameters betweeu the groups. Results: The clustering method allocated patients betweeu three clusters: depeudeut, non-dependeut with instrumental fuuctioual disability (IFD) aud non-depeudeut without IFD. Dependence, as defined by these clusters, significantly correlates with age, resideutial setting, MMSE, patient’ s aud caregiver’ s quality of life aud total costs. Cost modelliug showed that 74% of the variability of costs was explaiued by disability, iustitutioualisatiou aud the iuteractiou betweeu disability aud iustitutioualisation Severity showed 110 direct iuflueuce 011 cost. However its effect was already takeu iuto account through its iuflueuce 011 disability. Conclusion: This uew classification allows a more sensitive patient evaluation It should be used to assess the beuefit of a uew strategy oii patieiit progression

mP4

012

Effect beta

of memantine peptide in cell

on levels cultures

of the

amyloid

D.K. Lahiri’ , G.M. Alley’, C. Morgan’ , P. Bauerjee2, M. Farlow3. ‘Indiana University School of Medicine, Department of Psychiatry, Indianapolis, i2S.A.; ‘Forest Laboratories, Inc., Department of Pharmacology and Toxicology, Jersey City, i2S.A.; 31ndiana University School of Medicine, Department of Neurology, Indianapolis, i2S.A. Our objective was to study the effects of memautiue, a moderate affinity, uncompetitive NMDA receptor amagonist, 011 the processing of beta-amyloid precursor protein (APP) aud levels of amyloid-fi peptide (A@ in ueuroual cell lines. Oue curreut therapeutic strategy for Alzheimer’ s disease (AD) is to reduce levels of the toxic Afi, which is derived from APP. APP is processed by three proteases termed a-, fi- aud y-secretases. The a-secretase cleaves APP withiu Afi to the secreted derivative sAPPa, precluding Afi formation In contrast, cleavages of APP by fi- aud y-secretases result in iutact Afi production, leading to amyloid deposition Since Afi-ueurotoxicity is greatly euhauced

neurological

disorders

s391

in the presence of NMDA, we are iuterested in examining the effects of memautiue, which is uudergoiug clinical trials in the US for the treatment of AD, 011 APP processing pathways. Humau ueuroblastoma (SK-N-SH) cells were treated with memautiue or vehicle for 2448 hours. The levels of secreted sAPP aud Afi1-40 in the couditioued media aud the total intracellular APP were measured by westeru immuuoblottiug aud sandwich-based ELISA assays. Treatment of human ueuroblastoma cells with memautiue (25 FM) resulted in decreased Afi1-40 levels in the couditioued media (-25% from control). Memautiue also exhibited a treud to decrease levels of sAPP in the couditioued media without affecting levels of total intracellular APP. Cell viability aud toxicity as determilled by MTT aud LDH assays were uot affected by memautiue at the above couceutratious for up to 48 hours. A decrease in Afi1-40 levels without a coucomitaut iucrease in cellular APP levels by memautiue suggests that it may inhibit the amyloidogeuic (amyloid formation) pathway.

mP4

013

GSK3fi over-expressing for Alzheimer’s disease?

mice

- a mouse

model

P.A. Schiitt, A. Rask, Y. Nilsson, A. Stafluud, R.V Bhat. Local Discovery Research Area CNS & Pain Control, Bioscience, Huddinge, Sweden Alzheimer’ s disease (AD) is a progressive neurodegenerative disease, characterized by severe amnesia for recently experienced eve&, i.e. declarative memory. Existing auimal models of AD do uot show all the pathological features of the disease. However, some trausgeuic mice, such as GSK3fi over-expressing mice, mimic some of the major pathological features of AD i.e. tau hyperphosphorylatiou, neurodegeueratiou aud gliosis (GruukeIqbal et al., 1986). The aim of the present study was to iuvestigate if GSK3fi overexpressing animals also exhibited a fuuctioual deficit, resembling that of earlier stages of AD. GSK3fi over-expressing animals were geuerated as described by Avila aud co-workers (Lucas et al., 2001), with the modification of a humau GSK3fi geue iustead of the Xeuopus counterpart. The Morris swim maze was chosen as a relevant behavioral model, since it is depeudeut 011 the integrity of au iutact hippocampal fonnatioii. The animals were divided iuto two groups, animals with a geuetic driver for the GSK3fi-gene (litter-mates, n=16) aud animals with both driver aud geue (trausgeues, 11~14). Both males aud females were used since 110 sex-differences were observed withiu the two groups. The animals were pre-trained for oue week (four trials/day, four starting-positions, cut-off time 90 s) using a visual, randomly placed, cued platfonn, theu allowed a period of two weeks of rest. This was followed by oue week of traiuiug (hiddeu platfonn, fixed position, random star&g positions). Memory was tested in a probe trial (platform removed) 3 days after the last traiuiug session Surprisingly, 110 significant difference (repeated measures ANOVA) was found betweeu the two groups with regard to latency to find the platfonn (P=O.39), swim length (P=O.O57), swim speed (P=O.79), or time spent in traiuiug quadraut during the probe trial (P~0.19, unpaired t-test). To rule out the possibility of a motor dysfuuctiou in the trausgeuic animals, they were tested in commercially available computerized locomotor boxes. The prelimiuary results indicate that these animals have au iucreased motor activity (only trausgeues tested). Further studies have beeu iuitiated to iuvestigate this observation Furthennore,