RESUMO
Tau aggregation is a common feature of neurodegenerative diseases such as Alzheimer's disease, and hyperphosphorylation of tau has been implicated as a fundamental pathogenic mechanism in this process. To examine the impact of cdk5 in tau aggregation and tangle formation, we crossed transgenic mice overexpressing the cdk5 activator p25, with transgenic mice overexpressing mutant (P301L) human tau. Tau was hyperphosphorylated at several sites in the double transgenics, and there was a highly significant accumulation of aggregated tau in brainstem and cortex. This was accompanied by increased numbers of silver-stained neurofibrillary tangles (NFTs). Insoluble tau was also associated with active GSK. Thus, cdk5 can initiate a major impact on tau pathology progression that probably involves several kinases. Kinase inhibitors may thus be beneficial therapeutically.
Assuntos
Tronco Encefálico/metabolismo , Córtex Cerebral/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Emaranhados Neurofibrilares/enzimologia , Proteínas tau/metabolismo , Animais , Tronco Encefálico/patologia , Córtex Cerebral/patologia , Quinase 5 Dependente de Ciclina , Quinases Ciclina-Dependentes/genética , Indução Enzimática/genética , Regulação Enzimológica da Expressão Gênica , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Fosforilação , Proteínas tau/genéticaRESUMO
Plaques containing beta-amyloid (Abeta) peptides are one of the pathological features of Alzheimer's disease, and the reduction of Abeta is considered a primary therapeutic target. Amyloid clearance by anti-Abeta antibodies has been reported after immunization, and recent data have shown that the antibodies may act as a peripheral sink for Abeta, thus altering the periphery/brain dynamics. Here we show that peripheral treatment with an agent that has high affinity for Abeta (gelsolin or GM1) but that is unrelated to an antibody or immune modulator reduced the level of Abeta in the brain, most likely because of a peripherally acting effect. We propose that in general, compounds that sequester plasma Abeta could reduce or prevent brain amyloidosis, which would enable the development of new therapeutic agents that are not limited by the need to penetrate the brain or evoke an immune response.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Amiloidose/tratamento farmacológico , Gangliosídeo G(M1)/farmacologia , Gelsolina/farmacologia , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/sangue , Precursor de Proteína beta-Amiloide/genética , Amiloidose/metabolismo , Amiloidose/patologia , Animais , Encéfalo/metabolismo , Feminino , Gangliosídeo G(M1)/administração & dosagem , Gangliosídeo G(M1)/metabolismo , Gelsolina/administração & dosagem , Gelsolina/metabolismo , Injeções Intraperitoneais , Masculino , Proteínas de Membrana/genética , Camundongos , Mutação , Presenilina-1RESUMO
Recent evidence strongly suggests a role for cholesterol and apolipoprotein E in the etiology of Alzheimer's disease. We have demonstrated the co-localization of cholesterol and apolipoprotein E with beta-amyloid immunoreactivity and thioflavin S immunofluorescence in AD type plaques of a transgenic mouse model. Cholesterol and apolipoprotein E co-localized to the core of thioflavin S-positive (fibrillar) plaques, but not thioflavin S-negative (diffuse) plaques from an early age. By 18 months of age, there was extensive coverage of fibrillar plaques immunopositive for apolipoprotein E and cholesterol oxidase. These findings support evidence that cholesterol and apolipoprotein E are involved in fibrillar plaque formation or maintenance, and suggest that cholesterol may impact amyloid formation extracellularly, as well as through an intracellular effect.