Project description
Determining sporadic Alzheimer’s disease mechanisms
Although sporadic Alzheimer’s disease (AD) is associated with the majority of AD cases and affects exclusively old people, there is limited knowledge about the mechanistic relationship between ageing and AD pathology. Scientists of the University of Innsbruck in Austria recently discovered that direct conversion of human fibroblasts into induced neurons (iNs) maintains signatures of ageing, and they are developing a patient-based iN model for AD. The EU-funded AGEMEC project will determine the earliest and possibly curable disease mechanisms and seek to understand the mechanisms that condition cellular ageing and the development of AD to elaborate new treatment strategies for the disease. In addition, the project will take into consideration the knowledge acquired in the field of cancer to better understand AD.
Objective
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.
Fields of science
Programme(s)
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Funding Scheme
ERC-STG - Starting GrantHost institution
6020 Innsbruck
Austria