RESUMEN
Missense point mutations, duplication and triplication in the alpha-synuclein (alphaSYN) gene have been identified in familial Parkinson's disease (PD). Familial and sporadic PD show common pathological features of alphaSYN pathologies, e.g., Lewy bodies (LBs) and Lewy neurites (LNs), and a loss of dopaminergic neurons in the substantia nigra that leads to motor disturbances. To elucidate the mechanism of alphaSYN pathologies, we generated TgalphaSYN transgenic mice overexpressing human alphaSYN with double mutations in A30P and A53T. Human alphaSYN accumulated widely in neurons, processes and aberrant neuronal inclusion bodies. Sarcosyl-insoluble alphaSYN, as well as phosphorylated, ubiquitinated and nitrated alphaSYN, was accumulated in the brains. Significantly decreased levels of dopamine (DA) were recognized in the striatum. Motor impairment was revealed in a rotarod test. Thus, TgalphaSYN is a useful model for analyzing the pathological cascade from aggregated alphaSYN to motor disturbance, and may be useful for drug trials.
Asunto(s)
Encéfalo/metabolismo , Actividad Motora/fisiología , Neuronas/metabolismo , alfa-Sinucleína/genética , Acetilcolina/metabolismo , Animales , Western Blotting , Encéfalo/patología , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Humanos , Inmunohistoquímica , Cuerpos de Inclusión/metabolismo , Ratones , Ratones Transgénicos , Mutación , Neuronas/citología , Fosforilación , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Prueba de Desempeño de Rotación con Aceleración Constante , Serotonina/metabolismo , UbiquitinaciónRESUMEN
Missense mutations of the tau gene cause autosomal dominant frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), an illness characterized by progressive personality changes, dementia, and parkinsonism. There is prominent frontotemporal lobe atrophy of the brain accompanied by abundant tau accumulation with neurofibrillary tangles and neuronal cell loss. Using a hamster prion protein gene expression vector, we generated several independent lines of transgenic (Tg) mice expressing the longest form of the human four-repeat tau with the R406W mutation associated with FTDP-17. The TgTauR406W 21807 line showed tau accumulation beginning in the hippocampus and amygdala at 6 months of age, which subsequently spread to the cortices and subcortical areas. The accumulated tau was phosphorylated, ubiquitinated, conformationally changed, argyrophilic, and sarcosyl-insoluble. Activation of GSK-3beta and astrocytic induction of mouse tau were observed. Astrogliosis and microgliosis correlated with prominent tau accumulation. Electron microscopic examination revealed the presence of straight filaments. Behavioral tests showed motor disturbances and progressive acquired memory loss between 10 to 12 months of age. These findings suggested that TgTauR406W mice would be a useful model in the study of frontotemporal dementia and other tauopathies such as Alzheimer's disease (AD).
Asunto(s)
Corteza Cerebral/metabolismo , Proteínas tau/biosíntesis , Proteínas tau/genética , Amígdala del Cerebelo/metabolismo , Animales , Astrocitos/metabolismo , Conducta Animal , Western Blotting , Encéfalo/metabolismo , Cricetinae , Vectores Genéticos , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Hipocampo/metabolismo , Humanos , Ratones , Ratones Transgénicos , Microglía/metabolismo , Microscopía Electrónica , Mutación , Mutación Missense , Fosforilación , Priones/metabolismo , Conformación Proteica , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Transgenes , Ubiquitina/metabolismoRESUMEN
The antidepressant effect of Sho-ju-sen, a Japanese herbal medicine composed of extracts of three herbs; kumazasa leaf (Sasa Kurinensis Makino et Sibata), Japanese red pine leaf (Pinus densiflora Sieb. et Zucc) and ginseng radix (Panax ginseng C.A. Meyer), was assessed using a learned helplessness model in mice. The learned helplessness was produced by presenting 120 unavoidable/inescapable shocks for 3 days to the mouse in a shuttle box, and the avoidance training was carried out on day 4. Compared with the control group given tap water, free consumption of Sho-ju-sen (1%, 3% and 10%) for 21 days resulted in a significant amelioration of the response rate at 1% and 3%, and both the response rate and % avoidance at 10%. Although Sho-ju-sen (10%) caused no significant effect following the 7-day intake, it ameliorated the response rate following the 14-day intake. The extract of Japanese red pine leaf, but not kumazasa leaf or ginseng radix, mildly improved the response rate. Learned helplessness was significantly and dose-dependently reduced by imipramine (10 and 30 mg/kg i.p.), while only mildly by diazepam (1 mg/kg p.o.). These results suggest that a long-term consumption of Sho-ju-sen is effective for the amelioration of depression, and the effectiveness is derived mainly from the extract of Japanese red pine leaf.
Asunto(s)
Antidepresivos/farmacología , Medicamentos Herbarios Chinos/farmacología , Desamparo Adquirido , Fitoterapia , Plantas Medicinales , Animales , Antidepresivos/administración & dosificación , Antidepresivos/uso terapéutico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/uso terapéutico , Masculino , Ratones , Ratones Endogámicos , Panax , Pinus , Extractos Vegetales/administración & dosificación , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Hojas de la Planta , SasaRESUMEN
To clarify whether amyloid beta protein (Abeta) amyloidosis induces a disturbance of cholinergic system leading to long-term memory deficits, we continuously examined memory disturbance using the passive-avoidance task, and measured Abeta burden and concentrations of acetylcholine in the brain of APPsw transgenic mice. Repetitive retention trials of the passive-avoidance task showed that the long-term memory impairment in APPsw mice appeared from approximately 7.75 months old and progressively advanced. Significant decreases in acetylcholine levels were found in the brains of 10-month-old mice. A few senile plaques appeared in the cerebral cortex and the hippocampus at 8 months old, and increased in size and number with aging. The concentrations of brain Abeta40/42(43) gradually increased from 8 months old and exponentially increased thereafter. Advance of long-term memory disturbance was closely correlated with Abeta40/42(43) burden. These findings suggested that Abeta accumulation induced long-term memory impairment and disturbance of the cholinergic system, and that the passive-avoidance task and measuring acetylcholine were useful methods for evaluating this mouse model as well as Abeta accumulation.
Asunto(s)
Acetilcolina/metabolismo , Precursor de Proteína beta-Amiloide/biosíntesis , Encéfalo/metabolismo , Trastornos de la Memoria/metabolismo , Factores de Edad , Precursor de Proteína beta-Amiloide/genética , Animales , Humanos , Trastornos de la Memoria/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Tiempo de Reacción/fisiologíaRESUMEN
The anxiolytic-like effects of Ginkgo biloba extract (GBE) and its four terpenoid components (ginkgolide-A, ginkgolide-B, ginkgolide-C, and bilobalide) were assessed using the elevated plus-maze test in mice. Administration of GBE as a single oral dose (0.5 or 1 g/kg, po) caused a state of suppressed motor activity and, thus, shortened the time spent in the open-sided arms. However, when GBE (0.063-1 g/kg, po) was administered daily for 7 days and the plus-maze test was carried out 24 h after the final administration, the time spent in the open-sided arms was prolonged, with the peak anxiolytic-like effect at 0.125 g/kg. A combination of seven-day administration of GBE (0.125 g/kg) and a single dose of diazepam (1 mg/ kg, po, 10 min before testing) enhanced the anxiolytic-like effect. Flumazenil (0.3 mg/kg, ip, 10 min before testing) blocked the effect of diazepam, but not of GBE. Daily administration of ginkgolide-A (1 or 2 mg/kg, po) resulted in an anxiolytic-like effect by the third treatment, with the maximal effect observed after the fifth administration. Neither ginkgolide-B, ginkgolide-C, nor bilobalide produced any anxiolytic-like effects. At doses higher than 0.5 g/kg, GBE not only inhibited motor activity but also suppressed active avoidance behavior, reduced caffeine-induced stimulation, and enhanced pentobarbital-induced sleep, while ginkgolide-A (up to 20 mg/kg) did not exhibit these effects. Diazepam (1 mg/kg) is known to enhance pentobarbital-induced sleep. These results suggest that GBE produces a significant anxiolytic-like effect following repeated administration and that ginkgolide-A is most likely responsible for this effect. There are also indications that although GBE exerts a sedative effect at comparatively higher doses, ginkgolide-A has a relatively weak tendency to produce benzodiazepine-like side effects.