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.
Chaudhry Luqman Abid (PhD): Glycosylation of Alzheimer-associated proteins in the context of microglia-mediated inflammation and disturbed blood-brain barrier functions
Age-dependent disturbed immune plasticity of microglia and disturbed blood-brain barrier BBB functionality may provide early phenotypes of late-onset Alzheimer's disease (LOAD). LOAD is age-related and the number of patients grows steadily not only in Germany. We published mutations (TREM2, ABCA7) and described an association (CD33) of microglia- and BBB-related genes that confer a risk for LOAD. These proteins undergo LOAD-associated posttranslational modifications (PTMs) including glycosylation and particularly sialylation. We therefore ask how glycosylation of CD33, TREM2, and ABCA7 contribute to LOAD and how are alterations in these PTMs relate to cellular ageing mechanisms. In this project, we will analyse the impact of mutations on PTMs of the proteins. We established LOAD-specific induced pluripotent stem (iPS) cell models for microglia and BBB cultures. We will apply these in vitro models for analysing the impact of PTMs on the functionality of TREM2, ABCA7, and CD33 and their contribution to the onset of LOAD.
Hendrik Schlüter (MD):The impact of protein homeostasis in the clearance of amyloid beta peptide at the aged blood-brain barrier
The blood-brain barrier (BBB) forms a selective gateway for the entrance and exit of all factors and molecules in and out of the brain. It is not yet fully understood why impaired BBB function is associated with various neurodegenerative and immunological diseases and why old age has a negative impact on BBB function in this context. Nevertheless, the respective trigger proteins must cross the BBB at a certain point in time. In Alzheimer’s disease, the trigger protein is amyloid beta (Aß), a polypeptide of 37-49 amino acids, which is generated by proteolysis from the Amyloid-beta precursor protein (APP). A major pathway of protein degradation is executed by lysosomes, which are organelles containing a huge number of hydrolases including peptidases. Lysosomes are mainly involved in the degradation of extracellular material that enter the cell by endocytosis but are also involved in the homeostasis of other organelles and cellular proteins, including mitophagic and autophagic processes in an age dependent manner. Thus, we will address the question, whether in our induced pluripotent stem cell-derived BBB models these processes are affected by age and/or genetic preposition that are associated with Alzheimer’s disease.