A subtle but chronic alteration in metabolic balance between amyloid-␤ peptide (A␤) anabolic and catabolic activities is thought to cause A␤ accumulation, leading to a decade-long pathological cascade of Alzheimer disease. However, it is still unclear whether a reduction of the catabolic activity of A␤ in the brain causes neuronal dysfunction in vivo. In the present study, to clarify a possible connection between a reduction in neprilysin activity and impairment of synaptic and cognitive functions, we cross-bred amyloid precursor protein (APP) transgenic mice (APP23) with neprilysin-deficient mice and biochemically and immunoelectron-microscopically analyzed A␤ accumulation in the brain. We also examined hippocampal synaptic plasticity using an in vivo recording technique and cognitive function using a battery of learning and memory behavior tests, including Y-maze, novel-object recognition, Morris water maze, and contextual fear conditioning tests at the age of 13-16 weeks. We present direct experimental evidence that reduced activity of neprilysin, the major A␤-degrading enzyme, in the brain elevates oligomeric forms of A␤ at the synapses and leads to impaired hippocampal synaptic plasticity and cognitive function before the appearance of amyloid plaque load. Thus, reduced neprilysin activity appears to be a causative event that is at least partly responsible for the memory-associated symptoms of Alzheimer disease. This supports the idea that a strategy to reduce A␤ oligomers in the brain by up-regulating neprilysin activity would contribute to alleviation of these symptoms. Accumulation of amyloid-␤ peptide (A␤)4 is a triggering event leading to a decade-long pathological cascade of Alzheimer disease (AD) (1, 2). A subtle but chronic alteration in metabolic balance between A␤ anabolic and catabolic activities could result in A␤ accumulation and change monomeric A␤ to pathogenic forms (3,4). Neprilysin is an A␤-degrading enzyme first identified as a major in vivo peptidase capable of hydrolyzing synthetic multiple-radiolabeled A␤ injected into rat hippocampus (5). A genetic deficiency in neprilysin results in an elevation of A␤ levels in the mouse brain (6). Transgenic or viral expression of neprilysin in the brains of amyloid precursor protein (APP) transgenic mice consistently leads to marked attenuation of A␤ pathology (7-9). The exposure of APP transgenic mice to an enriched environment is reported to result in pronounced deceleration in cerebral A␤ levels and amyloid deposits with a concomitant elevation of brain neprilysin activity (10). Neprilysin is a presynaptic membrane-associated ectoenzyme with an extracellular active site, and it is involved in A␤ degradation at presynaptic sites (9,11,12). A recent study showed that somatostatin causes selective reduction of A␤ 42 by promoting the surface appearance of neprilysin on the presynaptic membrane (13). Down-regulation of neprilysin in the hippocampus and cerebral cortex with aging (14,15) and at an early stage of AD development (15-17) suggests a cl...

There is no established genetic model of bipolar disorder or major depression, which hampers research of these mood disorders. Although mood disorders are multifactorial diseases, they are sometimes manifested by one of pleiotropic effects of a single major gene defect. We focused on chronic progressive external ophthalmoplegia (CPEO), patients with which sometimes have comorbid mood disorders. Chronic progressive external ophthalmoplegia is a mitochondrial disease, which is accompanied by accumulation of mitochondrial DNA (mtDNA) deletions caused by mutations in nuclear-encoded genes such as POLG (mtDNA polymerase). We generated transgenic mice, in which mutant POLG was expressed in a neuron-specific manner. The mice showed forebrain-specific defects of mtDNA and had altered monoaminergic functions in the brain. The mutant mice exhibited characteristic behavioral phenotypes, a distorted day-night rhythm and a robust periodic activity pattern associated with estrous cycle. These abnormal behaviors resembling mood disorder were worsened by tricyclic antidepressant treatment and improved by lithium, a mood stabilizer. We also observed antidepressant-induced mania-like behavior and long-lasting irregularity of activity in some mutant animals. Our data suggest that accumulation of mtDNA defects in brain caused mood disorder-like mental symptoms with similar treatment responses to bipolar disorder. These findings are compatible with mitochondrial dysfunction hypothesis of bipolar disorder.

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Background and purpose: Accumulated evidence suggests that oxidative stress is involved in amyloid b (Ab)-induced cognitive dysfunction. Silibinin (silybin), a flavonoid derived from the herb milk thistle (Silybum marianum), has been shown to have antioxidative properties; however, it remains unclear whether silibinin improves Ab-induced neurotoxicity. In the present study, we examined the effect of silibinin on the memory impairment and accumulation of oxidative stress induced by Ab25-35 in mice. , once a day, p.o.) was started immediately after the injection of Ab25-35. Locomotor activity was evaluated 6 days after the Ab25-35 treatment, and cognitive function was evaluated in a Y-maze and novel object recognition tests 6-11 days after the Ab25-35 treatment. The levels of lipid peroxidation (malondialdehyde) and antioxidant (glutathione) in the hippocampus were measured 7 days after the Ab25-35 injection. Key results: Silibinin prevented the memory impairment induced by Ab25-35 in the Y-maze and novel object recognition tests. Repeated treatment with silibinin attenuated the Ab25-35-induced accumulation of malondialdehyde and depletion of glutathione in the hippocampus. Conclusions and implications:Silibinin prevents memory impairment and oxidative damage induced by Ab25-35 and may be a potential therapeutic agent for Alzheimer's disease.

Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) function to remodel the pericellular environment. Their activation and regulation are associated with synaptic physiology and pathology. Here, we investigated whether MMP-2 and MMP-9 are involved in the rewarding effects of and sensitization to methamphetamine (METH) in animals, in which the remodelling of neural circuits may play a crucial role. Repeated METH treatment induced behavioural sensitization, which was accompanied by an increase in MMP-2 and MMP-9 activity in the brain. In MMP-2-and MMP-9-deficient mice [MMP-2-(-/-) and MMP-9-(-/-)], METH-induced behavioural sensitization and conditioned place preference, a measure of the rewarding effect, as well as METH-increased dopamine release in the nucleus accumbens (NAc) were attenuated compared with those in wild-type mice. In contrast, infusion of purified human MMP-2 into the NAc significantly potentiated the METH-increased dopamine release. The [ 3 H]dopamine uptake into striatal synaptosomes was reduced in wild-type mice after repeated METH treatment, but METH-induced changes in [ 3 H]dopamine uptake were significantly attenuated in MMP-2-(-/-) and MMP-9-(-/-) mice. These results suggest that both MMP-2 and MMP-9 play a crucial role in METHinduced behavioural sensitization and reward by regulating METH-induced dopamine release and uptake in the NAc.