Banerjee, P.K.

Luiten, P.G.M.

Nyakas, C.

Penke, B.

Szabó, R.

English

ARTS repository - University of Groningen

   University of GroningenMemantine Rescues Cholinergic Neurons from the Neurotoxic Effects of β-Amyloid (Aβ1-42)Nyakas, C.; Szabó, R.; Penke, B.; Luiten, P.G.M.; Banerjee, P.K.Published in:European NeuropsychopharmacologyIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2006Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Nyakas, C., Szabó, R., Penke, B., Luiten, P. G. M., & Banerjee, P. K. (2006). Memantine RescuesCholinergic Neurons from the Neurotoxic Effects of β-Amyloid (Aβ1-42). EuropeanNeuropsychopharmacology, S484-S484.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 20-06-2022S484 P.5.b Dementia and neurological disorders – Dementia disorders (basic)also reduced in memantine-treated media compared to control.These data suggest that memantine may affect APP processingand may potentially inhibit the accumulation of fibrillogenic Abpeptides.Conclusions: Further experiments are in progress to betterunderstand the mechanism of memantine’s effect on secretases.P.5.b.005 Memantine rescues cholinergic neurons fromthe neurotoxic effects of b-amyloid (Ab1−42)C. Nyakas1 °, R. Szabó1, B. Penke2, P.G.M. Luiten3,P.K. Banerjee4. 1Semmelweis University, Brain PhysiologyResearch Group, Budapest, Hungary; 2Szeged University,Department of Medical Chemistry, Szeged, Hungary; 3Universityof Groningen, Department of Molecular Neuroscience, Groningen,Netherlands; 4Forest Research Institute, Department ofPharmacology and Toxicology, Jersey City, USABackground: Memantine, a moderate affinity uncompetitiveNMDA receptor antagonist, is approved for the treatment ofAlzheimer’s disease (AD).Objective(s): The mechanisms by which memantine exerts itsbeneficial effects in AD are under investigation. Memantine hasbeen shown to provide neuroprotection and improve learning andmemory in several animal models. It has also been shown thattherapeutic doses of memantine reduce the levels of amyloidprecursor protein (APP), Ab1−40 and Ab1−42 peptides in humanneuroblastoma cells and in the rat primary cortical neurons.Methods: In this study, the neuroprotective effects of meman-tine were determined in rats with multiple unilateral Ab1−42lesions in the nucleus basalis magnocellularis (NBM) and parietalneocortex. The contralateral side of the brain served for control.Memantine (30mg/kg/day) was given orally via drinking waterstarting 3 days prior to lesioning and continued for 10 postoper-ative days. For behavioural analysis open-field exploration, novelobject recognition (attention) and one-trial step-through passiveavoidance learning paradigms were applied starting the analysis3 days after lesion. At the end of chronic memantine treatment(10 days after lesion) the animals were sacrificed for histolog-ical examination. The impact of amyloid peptide toxication oncholinergic cells was measured on the density of their axonsarriving to the neocortex. Cholinergic fibers were immunostainedby antibody against choline-acetyltransferase (ChAT). Activatedmicroglia was visualized by immunostaining against integrin aM[CD11b]. Image analyses of the immunostained anatomical struc-tures were carried out on a Quantimet Q-5001W computerizedimaging platform (Leica). Cholinergic fiber loss in the parietalneocortex layer V and the extent of microglial activation aroundthe NBM and cortical lesion sites were then evaluated.Results: Ab1−42 did not influence open-field behaviour butsignificantly decreased attention performance in the novel objectrecognition test by 60% and attenuated passive avoidance learn-ing by 67% (both significant at p< 0.05 level). Furthermore, itdecreased cholinergic fiber density in the target neocortical areaagainst sham-lesioned control (p< 0.005) and increased microglialactivation around the lesion areas, i.e. the increment in NBM was69% (p< 0.01) and in the neocortex 55% (p< 0.05). Memantinetreatment significantly attenuated the behavioural deficits in at-tention and passive avoidance learning and the performance ofmemantine-treated Ab1−42-lesioned group was not different fromthat of sham-lesioned control group. Memantine treatment pre-vented the Ab1−42-induced cholinergic fiber loss in the neocortex(p< 0.01) and the degree of fiber loss in the lesioned animals wasnot different from control. In addition, memantine significantlyattenuated microglial activation in the NBM (45%) and in theneocortical (35%) lesion sites.Conclusions: It is concluded from these studies that (1) pre-and postlesion continuous treatment with memantine attenuatesAb1−42-induced attention and learning deficits and (2) providesneuroprotection against Ab1−42 toxicity on cholinergic neuronsunder the conditions studied. A putative rescuing action of me-mantine on other neuron systems damaged by Ab1−42 as com-pared to cholinergic one merits further studies.References[1] Harkany T., Ábrahám I., Kónya C., Nyakas C., Zarándi M., PenkeB., Luiten P.G.M., 2000, Mechanisms of beta-amyloid neurotoxicity:Perspectives of pharmacotherapy, Rev. Neurosci., 11, 329–382.P.5.b.006 Age-dependent changes in hippocampalglutamate levels parallel learning impairmentin APP/PS1 transgenic miceR. Minkeviciene1, J. Ihalainen1, T. Malm1, V. Keksa-Goldsteine1,N. Leguit2, J. Glennon2, P.K. Banerjee3, H. Tanila4 °.1A.I. Virtanen Institute, University of Kuopio, Departmentof Neurobiology, Kuopio, Finland; 2Solvay Pharmaceuticals,Research Department, Weesp, Netherlands; 3Forest ResearchInstitute, Department of Pharmacology and Toxicology, JerseyCity, USA; 4University of Kuopio, Department of Neuroscienceand Neurology, Kuopio, FinlandBackground: Several lines of evidence suggest that inAlzheimer’s disease (AD), the neurotoxicity caused by b-amyloid(Ab) peptides may be related to elevated levels of glutamateand/or overactivity of the NMDA receptors. We have earlier shownthat memantine (an NMDA receptor antagonist) improves spatiallearning in APP/PS1 transgenic mice with elevated levels of Ab40and Ab42.Objective(s): In the present study, we determined the extracel-lular levels of glutamate in the hippocampus of APP/PS1 mice at6 and 16 months of age.Methods: Extracellular levels of glutamate were measured by invivo microdialysis under basal and stimulated conditions (in theabsence or presence of KCl, respectively). A separate group of6- and 16-month old APP/PS1 mice were also tested for spatiallearning in the water maze, and their brain Ab levels, amyloidplaque burden, microgliosis and astrogliosis were determined byELISA and immunocytochemistry.Results: APP/PS1 mice exhibited impaired performance in thewater maze at 16 months but not at 6 months. Although someplaques were present at 6 months of age, the brain levels ofAb40, Ab42 and plaque pathology increased significantly from 6months to 16 months. The basal extracellular glutamate level inthe hippocampus did not change at either age in APP/PS1 mice,but the stimulated glutamate level was slightly higher at 6 monthsand significantly lower at 16 months compared to respective age-matched wild-type controls. Basal but not peak glutamate releasecorrelated with the levels of vesicular glutamate transporters. Thenumber of reactive microglia was elevated at 16 but not at 6months.Conclusions: The time course of amyloid pathology and cog-nitive dysfunction in this APP/PS1 mouse line suggest that theobserved cognitive impairment in these mice was likely associated

Memantine Rescues Cholinergic Neurons from the Neurotoxic Effects of β-Amyloid (Aβ1-42)

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Memantine Rescues Cholinergic Neurons from the Neurotoxic Effects of β-Amyloid (Aβ1-42)

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