Descripción del proyecto
Determinar los mecanismos de la enfermedad de Alzheimer esporádica
Aunque la enfermedad de Alzheimer (EA) esporádica se asocia con la mayoría de los casos de EA y afecta exclusivamente a personas mayores, el conocimiento sobre la relación mecanicista entre el envejecimiento y esta enfermedad es limitado. Los científicos de la Universidad de Innsbruck (Austria) descubrieron recientemente que la conversión directa de fibroblastos humanos en neuronas inducidas mantiene las marcas del envejecimiento y están desarrollando un modelo de neurona inducida basada en el paciente para la EA. El proyecto AGEMEC, financiado con fondos europeos, determinará los mecanismos de la enfermedad más tempranos y que posiblemente puedan curarse, y buscará comprender los mecanismos que determinan el envejecimiento celular y el desarrollo de la EA para elaborar nuevas estrategias de tratamiento para la enfermedad. Además, el proyecto tendrá en cuenta el conocimiento adquirido en el campo del cáncer para comprender mejor la EA.
Objetivo
Sporadic Alzheimer’s Disease (AD) accounts for the overwhelming majority of all AD cases and exclusively affects people at old age. However, mechanistic links between aging and AD pathology remain elusive. We recently discovered that in contrast to iPSC models, direct conversion of human fibroblasts into induced neurons (iNs) preserves signatures of aging, and we have started to develop a patient-based iN model system for AD. Our preliminary data suggests that AD iNs show a neuronal but de-differentiated transcriptome signature. In this project, we first combine cellular neuroscience assays and epigenetic landscape profiling to understand how neurons in AD fail to maintain their fully mature differentiated state, which might be key in permitting disease development. Next, using metabolome analysis including mass spec metabolite assessment, we explore a profound metabolic switch in AD iNs that shows surprisingly many aspects of aerobic glycolysis observed also in cancer. While this link might represent an interesting connection between two age-dependent and de-differentiation-associated diseases, it also opens new avenues to harness knowledge from the cancer field to better understand sporadic AD. We further focus on identifying and manipulating key metabolic regulators that appear to malfunction in an age-dependent manner, with the ultimate goal to define potential targets and treatment strategies. Finally, we will focus on early AD mechanisms by extending our model to mild cognitive impairment (MCI) patients. An agnostic transcriptome and epigenetic landscape approach of glutamatergic and serotonergic iNs will help to determine the earliest and probably most treatable disease mechanisms of AD, and to better understand the contribution of neuropsychiatric risk factors. We anticipate that this project will help to illuminate the mechanistic interface of cellular aging and the development of AD, and help to define new strategies for AD.
Ámbito científico
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Programa(s)
Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
6020 Innsbruck
Austria