RESUMO
We assessed the integrity of cholinergic neurotransmission in parietal cortex of young adult (7 months) and aged (17 months) transgenic APPswe/PS1dE9 female mice compared to littermate controls. Choline acetyltransferase and acetylcholinesterase activity declined age-dependently in both genotypes, whereas both age- and genotype-dependent decline was found in butyrylcholinesterase activity, vesicular acetylcholine transporter density, muscarinic receptors and carbachol stimulated binding of GTP gamma S in membranes as a functional indicator of muscarinic receptor coupling to G-proteins. Notably, vesicular acetylcholine transporter levels and muscarinic receptor-G-protein coupling were impaired in transgenic mice already at the age of 7 months compared to wild type littermates. Thus, brain amyloid accumulation in this mouse model is accompanied by a serious deterioration of muscarinic transmission already before the mice manifest significant cognitive deficits.
Assuntos
Precursor de Proteína beta-Amiloide/genética , Mutação , Presenilina-1/genética , Receptores Muscarínicos/metabolismo , Transmissão Sináptica/genética , Acetilcolinesterase/metabolismo , Fatores Etários , Precursor de Proteína beta-Amiloide/metabolismo , Análise de Variância , Animais , Animais Geneticamente Modificados , Relação Dose-Resposta a Droga , Feminino , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Camundongos , N-Metilescopolamina/metabolismo , Piperidinas/metabolismo , Piperidinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Proteínas Vesiculares de Transporte de Acetilcolina/metabolismoRESUMO
We assessed baseline and KCl-stimulated glutamate release by using microdialysis in freely moving young adult (7 months) and middle-aged (17 months) transgenic mice carrying mutated human amyloid precursor protein and presenilin genes (APdE9 mice) and their wild-type littermates. In addition, we assessed the age-related development of amyloid pathology and spatial memory impaired in the water maze and changes in glutamate transporters. APdE9 mice showed gradual spatial memory impairment between 6 and 15 months of age. The stimulated glutamate release declined very robustly in 17-month-old APdE9 mice as compared to 7-month-old APdE9 mice. This age-dependent decrease in stimulated glutamate release was also evident in wild-type mice, although it was not as robust as in APdE9 mice. When compared to individual baselines, all aged wild-type mice showed 25% or greater increase in glutamate release upon KCl stimulation, but none of the aged APdE9 mice. There was an age-dependent decline in VGLUT1 levels, but not in the levels of VGLUT2, GLT-1 or synaptophysin. Astrocyte activation as measured by glial acidic fibrillary protein was increased in middle-aged APdE9 mice. Blunted pre-synaptic glutamate response may contribute to memory deficit in middle-aged APdE9 mice.
Assuntos
Envelhecimento/metabolismo , Precursor de Proteína beta-Amiloide/genética , Encéfalo/metabolismo , Ácido Glutâmico/metabolismo , Presenilina-1/genética , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo , Envelhecimento/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/biossíntese , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Astrócitos/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Regulação para Baixo/fisiologia , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/metabolismo , Gliose/fisiopatologia , Humanos , Masculino , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Placa Amiloide/genética , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Presenilina-1/metabolismo , Transmissão Sináptica/genéticaRESUMO
The present study assessed the influence of dietary lipids on accumulation of amyloid beta-peptide (Abeta) in the brain. Seven experimental diets with varying n-6/n-3-ratio, saturated and polyunsaturated fatty acid and cholesterol contents were fed to transgenic APPswe/PS1dE9 mice for 3-4 months beginning at a young adult age (6 months). Hippocampal Abeta levels were determined with ELISA and plaque load by using immunocytochemistry. A typical Western diet with 40% saturated fatty acids and 1% of cholesterol increased, while diets supplemented with docosahexaenoic acid (DHA) decreased Abeta levels compared to regular (soy oil based) diet. DHA diet also decreased the number of activated microglia in hippocampus and increased exploratory activity of transgenic mice, but did not improve their spatial learning in the water maze. The favorable effect of DHA on Abeta production was verified in two different cell lines. Regulation of dietary lipid intake may offer a new tool to reduce the risk of Alzheimer's disease at the population level.
