Memantine leads to behavioral improvement and amyloid reduction in Alzheimer's-disease-model transgenic mice shown as by micromagnetic resonance imaging - PubMed (original) (raw)

Comparative Study

. 2008 Sep;86(12):2784-91.

doi: 10.1002/jnr.21713.

Affiliations

Comparative Study

Memantine leads to behavioral improvement and amyloid reduction in Alzheimer's-disease-model transgenic mice shown as by micromagnetic resonance imaging

Henrieta Scholtzova et al. J Neurosci Res. 2008 Sep.

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.

(c) 2008 Wiley-Liss, Inc.

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Figures

Fig. 1

Fig. 1

Memantine significantly improved short-term memory in APP/PS1 mice. At 7 months of age (posttreatment), memantine-treated APP/PS1 mice performed as well as wild-type mice and significantly better than vehicle-treated APP/PS1 mice in a novel-object recognition test (★★ P = 0.008 compared with vehicle-APP/PS1 mice; one-way ANOVA). The exploration difference (%) was calculated by subtracting the percentage time spent by mice exploring the novel object from the percentage time spent exploring the familiar object (Bars indicate mean ± standard error of the mean).

Fig. 2

Fig. 2

Memantine decreased amyloid plaque burden in APP/PS1 mice. Micro-MRI scans of vehicle-treated APP/PS1 mice (A), memantine-treated APP/PS1 mice (B), and age-matched wild-type mice (C) at 7 months revealed fewer amyloid plaques (red arrows) in memantine-treated APP/PS1 mice compared with vehicle-treated APP/PS1 mice. Aβ plaques were detected with ex vivo µMRI after intracarotid injection of Gd-DTPA-Aβ1–40 peptide with manitol.

Fig. 3

Fig. 3

Average cortical T2★ values in treated vs. control APP/PS1 Tg mice. Quantification of cortical absolute T2★ values also demonstrated a memantine amyloid burden-lowering effect (★ P = 0.04; _t_-test) (Bars indicate mean ± standard error of the mean).

Fig. 4

Fig. 4

Memantine decreased hippocampal and cortical plaque burden in APP/PS1 mice. Histological analysis of APP/PS1–21 Tg mice showed the difference in Aβ burden. Thioflavin-S staining revealed more amyloid plaques in hippocampal sections of vehicle-treated APP/PS1 mice (A) compared with memantine-treated APP/PS1 mice (B). Similarly, Aβ immunostaining showed greater Aβ accumulation in hippocampal sections of vehicle-treated APP/PS1 mice (C) compared with sections from memantine-treated APP/PS1 mice (D). Cortical Aβ immunoreactivity also revealed differences between vehicle-treated (E) and memantine-treated (F) APP/PS1 mice. Scale bars = 200 µm.

Fig. 5

Fig. 5

Memantine reduced amyloid burden in APP/PS1 mice. Significant reduction in the area covered by Aβ (Aβ load) was observed in APP/PS1-Tg mice treated with memantine compared with age-matched Tg contol mice treated with vehicle. There was a 25% reduction in cortical amyloid burden (★ P = 0.047, two-tailed t-test) and a 28% reduction in hippocampal amyloid burden (# P = 0.021) as quantified by using an unbiased random sampling scheme and semiautomated image analysis system (Bars indicate mean ± standard error of the mean).

Fig. 6

Fig. 6

Memantine reduced cortical and hippocampal CD45 microglia in APP/PS1 mice. CD45 immunostaining followed by stereological analysis revealed fewer activated microglia in memantine-treated Tg animals compared with vehicle-treated animals, but the difference was not statistically significant (Bars indicate mean ± standard error of the mean).

Fig. 7

Fig. 7

Memantine reduced cortical and hippocampal GFAP in APP/PS1 mice. GFAP immunostaining followed by stereological analysis revealed fewer activated astrocytes in memantine-treated Tg animals compared with vehicle-treated animals, but the difference was not statistically significant (Bars indicate mean ± standard error of the mean).

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