RESUMO
The annual Alzheimer's Research UK (ARUK) Conference was hosted by the Manchester and North West Network Centre on March 8-9, 2016. In this report, we provide a summary of the research presented.
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Congressos como Assunto , Demência , Demência/tratamento farmacológico , Demência/etiologia , Demência/metabolismo , HumanosRESUMO
On 10-11 March 2015 University College London hosted the annual Alzheimer's Research UK Conference. This report provides an overview of the presentations and discussions that took place.
Assuntos
Congressos como Assunto , Demência , Animais , Demência/genética , Demência/patologia , Demência/fisiopatologia , Humanos , Reino UnidoRESUMO
Flavonoids, a group of dietary polyphenols have been shown to possess cognitive health benefits. Epidemiologic evidence suggests that they could play a role in risk reduction in dementia. Amyloid precursor protein processing and the subsequent generation of amyloid beta (Aß) are central to the pathogenesis of Alzheimer's disease, as soluble, oligomeric Aß is thought to be the toxic species driving disease progression. We undertook an in vitro screen to identify flavonoids with bioactivity at ßγ-mediated amyloid precursor protein processing, which lead to identification of a number of flavonoids bioactive at 100 nM. Because of known bioavailability, we investigated the catechin family further and identified epigallocatechin and (-)-epicatechin as potent (nanomolar) inhibitors of amyloidogenic processing. Supporting this finding, we have shown reduced Aß pathology and Aß levels following short term, a 21-day oral delivery of (-)-epicatechin in 7-month-old TASTPM mice. Further, in vitro mechanistic studies suggest this is likely because of indirect BACE1 inhibition. Taken together, our results suggest that orally delivered (-)-epicatechin may be a potential prophylactic for Alzheimer's disease.
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Doença de Alzheimer/genética , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Catequina/administração & dosagem , Catequina/farmacologia , Administração Oral , Animais , Encéfalo/metabolismo , Catequina/análogos & derivados , Células Cultivadas , Progressão da Doença , Masculino , Camundongos TransgênicosRESUMO
Soluble oligomeric amyloid ß peptide (Aß) generated from processing of the amyloid precursor protein (APP) plays a central role in the pathogenesis of Alzheimer's Disease (AD) and through actions at glutamatergic synapses affects excitability and plasticity. The physiological control of APP processing is not fully understood but stimulation of synaptic NMDA receptors (NMDAR) can suppress Aß levels through an ERK-dependent increase in α-secretase activity. AMPA-type glutamate receptors (AMPAR) couple to ERK phosphorylation independently of NMDAR activation raising the possibility that stimulation of AMPAR might similarly promote non-amyloidogenic APP processing. We have tested this hypothesis by investigating whether AMPAR directly regulate APP processing in cultured mouse cortical neurons, by analyzing APP C-terminal fragments (CTFs), soluble APP (sAPP), Aß levels, and cleavage of an APP-GAL4 reporter protein. We report that direct stimulation of AMPAR increases non-amyloidogenic α-secretase-mediated APP processing and inhibits Aß production. Processing was blocked by the matrix metalloproteinase inhibitor TAPI-1 but was only partially dependent on Ca(2+) influx and ERK activity. AMPAR can therefore, be added to the repertoire of receptors that couple to non-amyloidogenic APP processing at glutamatergic synapses and thus pharmacological targeting of AMPAR could potentially influence the development and progression of Aß pathology in AD.