Age-dependent Neuronal De-Differentiation in Alzheimer's Patient-Derived Induced Neurons
To investigate age-dependent mechanisms of sporadic Alzheimer's Disease (AD), my laboratory reprograms skin cells from AD patients and aged cognitively normal donors into induced neurons (iNs), and investigate these cells as a ‘brain model’ that is not only genetically unique to each patient, but that also biologically ‘remembers’ the age of the individual.
By measuring levels of all genes used by these iNs, we could already make the exciting discovery that the neurons from AD patients appear to have partially lost their memory regarding their own identity and function in the body; which in several ways shares molecular signatures of cancer. In this project we first aim to deeply characterize and understand this phenomenon of neuronal de-differentiation using a powerful next-generation sequencing and computation-assisted characterization of the epigenetic landscape of the iNs, as well as the iNs’ functional properties and survival strategies. Next, it is known from cancer that impaired cellular metabolism, the chemical processes that transacts energy and cellular building blocks, might drive cellular de-differentiation. In a second aim we will assess the metabolic pathways in AD and control iNs to hopefully unravel regulatory nodes that might serve as alterable switches for potential treatment strategies. We anticipate that our work will significantly benefit from the cancer research field, where scientists have worked for decades to develop drugs to prevent de-differentiation by targeting
The iN model system is the only human patient-specific neuronal model system known so far that allows for the integration of age-related mechanisms. We are determined to fully exploit this opportunity by generating iNs from a large number of clinically well-characterized patients, and analyzing these cells using several state of the art omics technologies. Ultimately, we work to try to find ways to give AD neurons their cellular memory back.
This project aims at bringing a substantially new perspective onto the pathogenesis of AD and might give rise to yet unexpected treatment strategies borrowed from the cancer field. The results from this research might holds exciting potential for personalized medicine approaches in the AD field, as well as for other
Traxler L, Lagerwall J, Eichhorner S, Stefanoni D, D'Alessandro A, Mertens J. Metabolism navigates neural cell fate in development, aging and neurodegeneration. Dis Model Mech. 2021 Aug 1;14(8):dmm048993. doi: 10.1242/dmm.048993. Epub 2021 Aug 4. PMID: 34345916; PMCID: PMC8353098.