Aging and neurodegeneration in a human brain tissue model

01.08.2022 bis 31.07.2026

Aging is the biggest risk factor for neurodegenerative diseases. In the brain glia cells are important drivers of aging and microglia-related inflammation leads to alterations in neuronal function. We hypothesize that microglia, neuron-intrinsic characteristics and soluble factors in the cerebrospinal fluid modulate neuronal function and drive neurodegeneration.
During the pilot phase we successfully established a human long-term ex vivo brain slice culture model of proteopathic disease, allowing for the first time to investigate the dynamics and molecular mechanisms of neurodegenerative disease in aged human tissue in unprecedented detail.
Taking this approach to the next level and dissecting the molecular-cellular underpinnings of reserve and vulnerability to proteopathy holds great potential for providing insight into disease pathogenesis with translational applicability to affected patients. For phase II of this project we will therefore focus on neurodegenerative insults in the context of different stages of human life and address not only cellular but also soluble factors that mediate cell-to-cell communication. We will significantly extent on our preceding work and create heterochronous brain slice cultures combining human brain tissue derived from patients of different age with progressively matured/aged microglia and CSF. Electrophysiology, targeted ‘omics’ and imaging will enable to identify how microglia drive age-related neuronal vulnerability, to reveal soluble (glial) aging factors interfering with neuronal function and how young/old neurons maintain/lose resilience to these processes. Thus, this project has the potential to contribute transformative insights into mechanisms underlying human aging and neurodegeneration that can uncover new avenues for therapy.