title: Memantine leads to behavioral improvement and amyloid reduction in Alzheimer's-disease-model transgenic mice shown as by micromagnetic resonance imaging.
abstract: Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to improve learning and memory in several preclinical models of Alzheimer's disease (AD). Memantine has also been shown to reduce the levels of amyloid beta (A beta) peptides in human neuroblastoma cells as well as to inhibit A beta oligomer-induced synaptic loss. In this study, we assessed whether NMDA receptor inhibition by memantine in transgenic mice expressing human amyloid-beta precursor protein (APP) and presenilin 1 (PS1) is associated with cognitive benefit and amyloid burden reduction by using object recognition, micromagnetic resonance imaging (micro MRI), and histology. APP/PS1 Tg mice were treated either with memantine or with vehicle for a period of 4 months starting at 3 months of age. After treatment, the mice were subjected to an object recognition test and analyzed by ex vivo micro MRI, and histological examination of amyloid burden. micro MRI was performed following injection with gadolinium-DTPA-A beta(1-40). We found that memantine-treated Tg mice performed the same as wild-type control mice, whereas the performance of vehicle-treated Tg mice was significantly impaired (P = 0.0081, one-way ANOVA). Compared with vehicle-treated animals, memantine-treated Tg mice had a reduced plaque burden, as determined both histologically and by micro MRI. This reduction in amyloid burden correlates with an improvement in cognitive performance. Thus, our findings provide further evidence of the potential role of NMDA receptor antagonists in ameliorating AD-related pathology. In addition, our study shows, for the first time, the utility of micro MRI in conjunction with gadolinium-labeled A beta labeling agents to monitor the therapeutic response to amyloid-reducing agents.
authors.affiliation: Department of Neurology, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Henrieta
authors.initials: H
authors.lastname: Scholtzova
authors.forename: Youssef Z
authors.initials: YZ
authors.lastname: Wadghiri
authors.forename: Moustafa
authors.initials: M
authors.lastname: Douadi
authors.forename: Einar M
authors.initials: EM
authors.lastname: Sigurdsson
authors.forename: Yong-Sheng
authors.initials: YS
authors.lastname: Li
authors.forename: David
authors.initials: D
authors.lastname: Quartermain
authors.forename: Pradeep
authors.initials: P
authors.lastname: Banerjee
authors.forename: Thomas
authors.initials: T
authors.lastname: Wisniewski
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D008279:Magnetic Resonance Imaging / Q000379:methods; D008559:Memantine / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology
chemical_list: D016564:Amyloid beta-Protein Precursor; D008559:Memantine