Research team "Molecular Neurodegeneration"
Univ.-Prof. Dr. rer. nat. Claus Pietrzik
Our research team focuses on the molecular and biochemical basis of neurodegeneration using Alzheimer’s disease as a model system. Through cell cultures and various animal models we analyze the pathobiochemical characteristics that cause or affect the progression of Alzheimer’s disease. Biochemical processes during the disease’s onset and progression are examined as well as possible new therapeutic approaches.
Alzheimer’s disease is a neurodegenerative disorder that is characterized by gradual cognitive decline ultimately resulting in dementia. Causative for its onset is the loss of synapses and an increased neuronal apoptosis. The pathological appearance consistent with neurodegeneration shows intracellular, neurofibrilliar tangles and extracellular amyloidal plaques in the brain of affected patients.
Current estimates predict that today 15 % of the worldwide population older than 65 and 50 % of those older than 80 are affected by Alzheimer’s disease. Worldwide, nearly 36 million people are believed to be living with Alzheimer's disease or dementia. That number isestimated to increase to 65 million by 2030 and 115 million by 2050. Consequently, by 2050, one in forty-five people may be living with Alzheimer’s disease.
Our team currently focuses on these major topics:
1. We are interested in the processing of the amyloid precursor protein (APP) and the physiological function of its metabolites.
The amyloid precursor protein (APP) family consists of type I transmembrane proteins of so far uncertain physiological functions. We were recently able to demonstrate that physiological dimerization of two APP molecules happens within the endoplasmic reticulum and further impacts localization and processing of another family member, APLP1. (Isbert et al. 2012, Journal of Cellular and Molecular Life Sciences). However, pathophysiological properties of APP have been much more in the focus during the last decades. Release of the amyloid-β (Aβ) peptides through proteolytic processing of the amyloid precursor protein (APP) is one of the main causes for the development of Alzheimer´s Disease (AD). The liberation of the Aβ peptide from APP is a complex process involving sequential cleavage events by different secretases. The major enzyme generating the N-terminus of Aβ was identified as BACE1 (β-site APP cleaving enzyme).
Recently we have identified a physiologically relevant interaction between the metalloprotease meprin β, a member of the astacin family of zinc endopeptidases, and APP by using a proteomics approach (in collaboration with Prof. Christoph Becker-Pauly, University of Kiel).
Cell culture based experiments further revealed APP as a putative substrate for meprin β in vivo.
In our lab we are currently investigating the functional role of meprin β in Alzheimer´s Disease since this enzyme appears to exhibit a BACE-like activity when overexpressed together with APP in mammalian cells, releasing N-terminal APP fragments of varying length in vitro and in vivo (Jefferson et al. 2011, Journal of Biological Chemistry).
To elucidate the role of meprin β in the pathogenesis of neurodegenerative diseases such as AD we are employing knock-out mouse models meprin-transgenic mice and cell biological experiments.
2. The molecular and biochemical role of the blood-brain-barrier (BBB) during Alzheimer's disease.
The blood-brain barrier (BBB) plays a crucial role in maintaining the brain homeostasis, preventing the brain from uncontrolled entrance or diffusion of potentially harmful molecules.
Several recent studies have also highlighted the importance of this barrier in neurodegenerative diseases such as Alzheimer's disease (AD) by regulating transport of the amyloid beta (Aβ) peptide via the low density lipoprotein receptor related protein 1 (LRP1).
Therefore, we are interested in the role of LRP1 as key receptor in Aβ transport across the blood-brain-barrier (BBB). We have established an in vitro blood-brain barrier transport model in our lab with primary mouse brain capillary endothelial cells (pMBCECs), which express functionally active LRP1.
Using transendothelial transport studies, we could recently demonstrate that LRP1 mediates bidirectional transcytosis of [125I]-Aβ1-40 across the BBB, whereas a knock-in mutation in the NPxYxxL endocytosis/sorting motif of endogenous LRP1 revealed a reduced Aβ transport from brain-to-blood and blood-to-brain compared to wild-type derived pMBCECs (Pflanzner et al. 2011, Neurobiology of Aging).
3. The functional role of the low-density lipoprotein receptor-related protein1 (LRP1) in the nervous system.
The low-density lipoprotein receptor (LDLR)-related protein 1 (LRP1) is a member of the LDLR family, frequently referred to as a large transmembrane receptor that can bind and internalize many functionally distinct ligands. Besides its role as a cargo-receptor, LRP1 has also been implicated in many signaling pathways.
We have shown in our group that LRP1 transmits extracellular signals via the N-methyl-D-aspartate (NMDA) receptor into the cell, resulting in an increased Erk1/2 phosphorylation (Martin et al. 2008, Journal of Biological Chemistry). We are currently using LRP1 knock-in mice, generated originally by Anton Roebroek (University Leuven, Belgium), which harbor mutations within the second C-terminal NPXY-motifs to investigate the impact of this mutation on NMDA receptor-mediated downstream signaling. Furthermore, we aim to elucidate whether lipoprotein receptor ligands might influence NMDA receptor activity through LRP1 and whether LRP1 conditional knock-out or knock-in mice show a specific NMDAR mediated behavior. Proteins binding to the intracellular parts of receptors involved in cell signaling function as scaffold proteins for signaling complexes, or downstream transducers within the cell.
We have identified novel binding partners of the lipoprotein receptor family using a yeast-mating based split-ubiquitin system. To validate these potential interactors we currently perform a variety of biochemical and cell culture experiments to elucidate their possible impact on lipoprotein receptor biology.