SP16

Principal Investigator: Matthias Jung & Thomas Hollemann (Institute of Physiological Chemistry, MLU Halle Wittenberg)

Maira Tariq (PhD): Proteostasis at the old blood-brain barrier: Implications for late-onset Alzheimer’s disease

Ageing of the blood-brain barrier (BBB) results from an accumulation of deficiencies with contributions of senescence, increased inflammation, and oxidative stress. Though age related changes in BBB function may also represent an adaptation for healthy ageing, but results in consequence in a dysfunctional BBB, which often correlate with the progressive cause of brain diseases like the development of neural diseases, including late-onset Alzheimer's disease (LOAD). Ubiquitination and autophagy target proteins via post-translational modifications for regulating the protein homeostasis of amyloid precursor protein (APP) and its harmful byproduct amyloid beta (Aβ) in neurons, but also in other cells of the neurovascular unit including the BBB. Further, APP expression is considered as a neuroprotective response to stress factors with impact on healthy aging. Therefore, we ask how ubiquitination and autophagy in the BBB do change during ageing and how do these changes contribute to the development of LOAD. We study ubiquitination and autophagy in induced pluripotent stem cell-derived brain-capillary endothelial cells, pericytes, astrocytes, microglia, and neurons.

Judith Olex (MD): Endothelial Aging at the BBB: Impact of disturbed proteostasis on SARS-Cov-2 infection

The central nervous system is separated from the circulating blood by specialized endothelial cells that form a selective barrier to maintain proper conditions for neuronal function and cellular homeostasis, the so-called blood-brain barrier (BBB). However, it is not yet clear how aging disrupts the barrier function of the BBB and how these changes are related to various age-related diseases such as Alzheimer's disease or increased susceptibility to viral infections. There are currently various hypotheses that describe different mechanisms that also regulate ageing as the cause of Alzheimer's disease. One hypothesis states that disorders of the ubiquitin-proteasome system (UPS) promote the degradation of the BBB. The UPS is a selective protein degradation pathway in which the small protein ubiquitin is used as a marker to rapidly degrade proteins in the cell. When the UPS is disrupted, certain proteins can no longer be degraded correctly and amyloid beta (Aß) accumulates and damages the cells. Age- and/or disease-related dysfunction of the BBB has a major impact on whether SARS-CoV-2 infects the CNS. It is important to point out that elderly people suffered severely from the complications of COVID-19 infection, which manifested in long-lasting symptoms and permanent impairment. Recent studies suggest that infection of BCECs and transmigration of infected immune cells are crucial for CNS infiltration. It is therefore likely that changes to the BBB are of particular importance for the development and progression of COVID-19. Using induced pluripotent stem cells (iPSCs), we aim to better understand which changes in UPS-mediated Aß degradation are present in BCECs during aging and COVID-19. Therefore, iPSC-derived BCECs from young and old donors as well as from Alzheimer's patients will be analyzed. We will transfect BCECs with SARS-Cov-2 isolates and mimic SARS-CoV-2 infection by treatment with the corresponding spike proteins.