Descrizione del progetto
Determinare i meccanismi della malattia di Alzheimer sporadica
Sebbene la malattia di Alzheimer (AD) sporadica sia associata alla maggior parte dei casi di AD e colpisca esclusivamente gli anziani, le conoscenze sulla relazione meccanicistica tra l’invecchiamento e la patologia dell’AD sono limitate. Gli scienziati dell’Università di Innsbruck in Austria hanno recentemente scoperto che la conversione diretta dei fibroblasti umani in neuroni indotti (iN) mantiene le firme dell’invecchiamento, e stanno sviluppando un modello di iN per l’AD basato sul paziente. Il progetto AGEMEC, finanziato dall’UE, determinerà i meccanismi iniziali e potenzialmente curabili della malattia e cercherà di comprendere i meccanismi che condizionano l’invecchiamento cellulare e lo sviluppo dell’AD per elaborare nuove strategie di trattamento per la malattia. Inoltre, il progetto prenderà in considerazione le conoscenze acquisite nel campo del cancro per comprendere meglio l’AD.
Obiettivo
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.
Campo scientifico
Parole chiave
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Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
6020 Innsbruck
Austria