- Department / Institute
- Translational Neurodegeneration and Centre of Neuropathology
- Subject area
- Mechanisms of Neurodegeneration
- Project titles
- see below
- Name of supervisor
- Prof. Dr. Jochen Herms
- Number of open positions
- Language requirements
- Fluent in English
(IELTS 6.5 or higher, TOFEL IBT 95 or higher)
- Academic requirements
- Applications should hold a Master degree in Biological Sciences, i.e. Molecular Biology, Biochemistry, Cell Biology, Medical Chemistry, Molecular Biotechnology or similar or Master in Medicine
1. Project: Function of the Amyloid precursor protein (APP) in astrocytes
Projects description: In addition to its central role in Alzheimer's pathogenesis the Amyloid precursor protein (APP) has an important function at the synapse. We and others have been able to show that a loss of APP affects synaptic transmission (Zou et al. EMBO J; 2016, Acta Neuropath. 2015). This has been primarily attributed to the loss of APP expression in neurons. However, we have shown that loss of APP also affects astrocyte function and that it affects the function of excitatory synapses (Luckner et al. iScience 2018; Montagna et al. Glia 2019). Furthermore, we have recently reported that astrocytes lacking APP show reduced Ca2+ transients, which is probably caused by altered mitochondrial function. We were able to confirm this finding in cell culture analyses, which now allows us to investigate the underlying molecular mechanisms. Within this project, we aim to analyze the effects and underlying molecular mechanisms of APP loss of function in astrocytes. Furthermore, we would like to investigate the consequences of APP loss of function in astrocytes on the structural synaptic plasticity of synaptic spines in GFP-labeled cortical neurons in vivo. In summary, these studies will provide a clear statement of the function of APP in astrocytes and contribute to a better understanding of the interplay between astrocytes and neurons.
2. Project: Effect of enhanced physical activity on the pathophysiology of Alzheimer’s disease via microglia
Accumulating evidence suggests that pathophysiology of AD could not be solely attributed to neuronal loss, but also glia-related immunological mechanisms in the central nervous system (CNS) Previously, we have demonstrated the critical role of microglia in AD pathophysiology (Peters et al. EMBO J 2019; Blume et al. J of Neuroinflamation 2018) During the last decade, numerous studies have demonstrated, that in both human and rodents, physical activity is associated with lower risk of AD , and attenuates AD pathophysiology in terms of decreasing inflammation and promoting cognition. However, how physical activity alters microglia in AD is insufficiently explored and understood. Here we will study the effect of physical activity on microglia using both in vivo and ex vivo methods (e.g., in vivo multiphoton imaging, in vivo electrophysiology, ex vivo super-resolution imaging, RNA sequencing, µPET Imaging etc.) on our AD mouse models subjected to voluntary running wheel system. We focus on genetic, protein and cellular alterations of microglia caused by physical activity, as well as the impact of these alterations on AD pathophysiology.
3. Project: Selective vulnerability of interneurons in a-synucleinopathy
It is now widely realized that Parkinson’s disease (PD) evolves into a multi-systems disorder that extends beyond the Substantia Nigra (SN), and that the disease vulnerable neuronal populations differ by brain area. Our current studies have shown cortical inhibitory neurons are highly vulnerable to a-syn toxicity following striatal seeding, and that loss of the subpopulation occurs in tandem to hyperactivity and synchronicity of the remaining neural network (Blumenstock et al. in press; EMBO Mol Med. 2017, Acta Neuropath 2019). The findings match well to clinical observations PD patients, in which the symptomatic motor cortex is characterized by a loss of intracortical inhibition. Conversely, the pre-symptomatic motorcortex exhibits minimal if any alterations of cortical excitability, but displays important alterations of cortical plasticity. Using VGat-CRE X Rosa-CAG-LSL-tdTomato-WPRE as a reporter line to identify GABAergic neurons and GCaMP6f under the pan-neuronal synapsin promoter, we aim to study discriminate disease vulnerable neurons from the general population. We hypothesize that deregulated activity of inhibitory neurons precedes their loss. This project uses functional in vivo 2-photon imaging and fiber based miniscopes (Marinkovic et al. Brain 2019).