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Memantine leads to behavioral improvement and amyloid reduction in Alzheimer's‐disease‐model transgenic mice shown as by micromagnetic resonance imaging
Author(s) -
Scholtzova Henrieta,
Wadghiri Youssef Z.,
Douadi Moustafa,
Sigurdsson Einar M.,
Li YongSheng,
Quartermain David,
Banerjee Pradeep,
Wisniewski Thomas
Publication year - 2008
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.21713
Subject(s) - memantine , nmda receptor , genetically modified mouse , magnetic resonance imaging , medicine , pharmacology , antagonist , amyloid (mycology) , psychology , pathology , neuroscience , chemistry , receptor , transgene , biochemistry , radiology , gene
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 β (Aβ) peptides in human neuroblastoma cells as well as to inhibit Aβ 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 (μMRI), 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 μMRI, and histological examination of amyloid burden. μMRI was performed following injection with gadolinium‐DTPA‐Aβ 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 μMRI. 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 μMRI in conjunction with gadolinium‐labeled Aβ labeling agents to monitor the therapeutic response to amyloid‐reducing agents. © 2008 Wiley‐Liss, Inc.