001 for WT). Exploration of two novel objects is not different between genotypes during acclimation (not shown). MTEP-treated APP/PS1 mice recover a novel object preference (Figure 7B; p < 0.001 for both WT and APP/PS1 with MTEP). A separate cohort of APP/PS1 was tested in the Morris water

maze. Without treatment, the APP/PS1 mice show greater latencies to locate a hidden platform relative to WT across learning trials (Figure 7C; RM-ANOVA, p < 0.001), and spend less time in the target quadrant during a probe trial for memory selleck compound 24 hr later (Figure 7D; ANOVA p < 0.001). In contrast, MTEP-treated APP/PS1 mice are indistinguishable from untreated WT or MTEP-treated WT mice in learning and memory (Figures 7C and 7D), but are different from untreated APP/PS1 (Figures 7C and 7D; p < 0.001). There is a significant interaction of genotype and drug (two-way RM-ANOVA in Figure 7C for APP/PS1 × MTEP interaction,

p < 0.001; two-way ANOVA in Figure 7D, p < 0.001). We also administered MTEP to 3XTg mice expressing mutant APP, PS1, and Tau (Oddo et al., 2003). this website At 8–9 months, these mice perform normally in the Morris water maze (not shown), but are impaired in novel object recognition (Figure 7E). After randomization to MTEP or vehicle, the 3XTg mice were assessed for novel object recognition (Figure 7G). MTEP-treated 3XTg mice show a novel object preference (p < 0.01), but vehicle-treated mice do not. Thus, MTEP reverses memory deficits in two transgenic AD mice. We considered whether improved memory with MTEP is correlated with a reversal of synaptic loss. A separate cohort of WT and APP/PS1

transgenic mice at 10 months age were treated for 10 days with MTEP, 15 mg/kg two many times a day. As expected, control APP/PS1 mice exhibit a 25%–30% decrease in area occupied by presynaptic synaptophysin and postsynaptic PSD-95 immunoreactivity in the dentate gyrus (Figures 8A–8C). The loss of stained synaptic area was fully rescued by a 10-day course of MTEP (Figures 8D and 8E). For WT mice, MTEP did not alter synaptic density. We also assessed synaptic density ultrastructurally, identifying synaptic profiles by the presence of a postsynaptic density and presynaptic vesicles (Figure 8F). Synapse density in transgenic dentate gyrus increased by 20% with MTEP treatment (Figure 8G). This study delineates a direct role for mGluR5 in Aβo-related pathophysiology. Of transmembrane PSD proteins, only mGluR5 supports coupling of Aβo-PrPC to Fyn activation. Intracellular calcium and protein translation are also linked to Aβo-PrPC engagement via mGluR5. An mGluR5 dependence of signaling is observed for TBS-soluble extracts of AD brain as well as synthetic Aβo, emphasizing the disease relevance. A coreceptor role for mGluR5 is required for dendritic spine loss and transgenic memory impairment. Together, these findings delineate mGluR5 activation as a critical step in Aβo signal transduction with potential for therapeutic intervention.