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The antiamnesic and neuroprotective activities of the new aminotetrahydrofuran derivative tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride (ANAVEX1-41), a nonselective muscarinic receptor ligand and s 1 protein activator, were examined in mice injected intracerebroventricularly with amyloid b [25][26][27][28][29][30][31][32][33][34][35] ) peptide (9 nmol). Ab 25-35 impaired significantly spontaneous alternation performance, a spatial working memory, and passive avoidance response. When ANAVEX1-41 (1-1000 mg/kg i.p.) was administered 7 days after Ab 25-35 , ie, 20 min before the behavioral tests, it significantly reversed the Ab 25-35 -induced deficits, the most active doses being in the 3-100 mg/kg range. When the compound was preadministered 20 min before Ab 25-35 , ie, 7 days before the tests, it prevented the learning impairments at 30-100 mg/kg. Morphological analysis of corticolimbic structures showed that Ab 25-35 induced a significant cell loss in the CA1 pyramidal cell layer of the hippocampus that was prevented by ANAVEX1-41 (100 mg/kg). Increased number of glial fibrillary acidic protein immunopositive cells in the retrosplenial cortex or throughout the hippocampus revealed an Ab 25-35 -induced inflammation that was prevented by ANAVEX1-41. The drug also prevented the parameters of Ab 25-35 -induced oxidative stress measured in hippocampus extracts, ie, the increases in lipid peroxidation and protein nitration. ANAVEX1-41, however, failed to prevent Ab 25-35 -induced caspase-9 expression. The compound also blocked the Ab 25-35 -induced caspase-3 expression, a marker of apoptosis. Both the muscarinic antagonist scopolamine and the s 1 protein inactivator BD1047 prevented the beneficial effects of ANAVEX1-41 (30 or 100 mg/kg) against Ab 25-35 -induced learning impairments, suggesting that muscarinic and s 1 targets are involved in the drug effect. A synergic effect could indeed account for the very low active doses measured in vivo. These data outline the therapeutic potential of ANAVEX1-41 as a neuroprotective agent in Alzheimer's disease.

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In Alzheimer's disease (AD), the expression of matrix metalloproteases (MMPs), which are capable of degrading extracellular matrix proteins, is increased in the brain. Previous studies with cultured glial cells have demonstrated that amyloid ␤ (A␤) protein can induce the expression of MMPs, which could be involved in the degradation of A␤. In the present study, we investigated the role of MMP-2 and MMP-9 in cognitive impairment induced by the injection of A␤ in mice. The intracerebroventricular injection of A␤25-35, A␤1-40, and A␤1-42, but not A␤40-1, transiently increased MMP-9, but not MMP-2, activity and protein expression in the hippocampus. Immunohistochemistry revealed the expression of MMP-9 to be increased in both neurons and glial cells in the hippocampus after A␤ treatment. The A␤-induced cognitive impairment in vivo as well as neurotoxicity in vitro was significantly alleviated in MMP-9 homozygous knockout mice and by treatment with MMP inhibitors. These results suggest the increase in MMP-9 expression in the hippocampus to be involved in the development of cognitive impairment induced by A␤1-40. Thus, specific inhibitors of MMP-9 may have therapeutic potential for the treatment of AD. Our findings suggest that, as opposed to expectations based on previous findings, MMP-9 plays a causal role in A␤-induced cognitive impairment and neurotoxicity.Alzheimer's disease (AD), the most common neurodegenerative disorder in humans, is characterized by deterioration of cognitive and mental functions, including learning and memory. The formation of extracellular deposits of amyloid ␤ (A␤) peptide, leading to the formation of neuritic plaques and neurofibrillary tangles in the cortex and hippocampus, is a prominent pathological feature of AD (Yamada and Nabeshima, 2000;Selkoe and Schenk, 2003). A␤, a spontaneously aggregating peptide of 39 to 43 amino acids, is the primary protein component of senile plaques, a pathological hallmark of AD (Hardy and Selkoe, 2002;Takuma et al., 2005a). Neurotoxicity mediated by A␤ has been well demonstrated both in vivo and in vitro and has been shown to involve oxidative stress, the perturbation of intracellular cal-

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