- Department/Institute:
- Center for Neuropathology and Prion Research
- Subject area:
- Neuroscience
- Name of supervisor:
- Jochen Herms / Lars Paeger
- Number of open position:
- 2
- Project title:
- Mechanisms of early non-cognitive symptoms in neurodegenerative diseases
- Project time plan:
- Full Doctoral Study-Model: 36 or 48 months
- Language requirements:
- fluent english
- Academic requirements:
- experience with animal research and wet lab work
Project description:
Neurodegenerative diseases including Alzheimer’s disease (AD) are currently affecting millions of people worldwide. While causal therapies are still not available, disease modifying interventions rely on the earliest possible diagnosis of the disease. Early non-cognitive symptoms often manifest decades before the characteristic cognitive decline in many neurodegenerative diseases. The locus coeruleus (LC) noradrenergic (noradrenalin; NA) system is affected particularly early in ND including AD, Parkinson’s disease, amyotrophic lateral sclerosis and primary tauopathies. In AD, the LC is the first site where aberrant tau hyperphosphorylation (pTau) is detected, putatively kickstarting the spread of tau throughout the central nervous system. Forebrain NA is almost solely derived from the LC and, as a function of its widespread axonal projections, regulates a variety of physiological processes including arousal and attention, sleep-wake-cycles, memory, energy homeostasis. Within recent years it has been shown that LC-NA other functions via the modulation of glia cells. Particularly, it has been shown that the LC indirectly controls cerebral flood flow (CBF) via the modulation of astrocytes, which in turn control vasoconstriction and dilation via astrocytic end-feet processes on blood vessels. We and others have shown that the LC-NA system is prone to early axonal degeneration on mouse models of neurodegenerative diseases. In our very latest study, we have shown that LC axon loss is underlying early olfactory deficits in a mouse model of AD and provide data towards similar processes in humans at early AD stages. A study from our colleagues on the campus depicts an early hypoperfusion phenotype in primary tauopathies particularly correlating with distant subcortical regions of taupathology10. For the present project, we hypothesize that early LC-NA system dysfunction and downstream altered noradrenergic control of CBF via astrocytes is the main reason for a hypoperfusion and ultimately unmatched energy requirements of the CNS. In order investigate this relationship, we use a mouse model of primary tauopathy11, which expresses human tau. To induce tau-pathology in specific anatomically located cell types, we have engineered a custom-built adeno-associated virus (AAV) which enables us to express mutant human tau using specific Cre-driver lines, such as a dopamine-β-hydroxylase Cre mouse, specific for NA neurons. We combine molecular biology, near super-resolution immunofluorescence and 3D reconstruction, multi-omic approaches (bulk and cell-typoe specific proteomics and transcriptomics) electrophysiology and state-of-the art in vivo methods such as longitudinal 2-photon microscopy and miniature endomicroscopy combined with optogenetics and animal behaviour9 and metabolic phenotyping. Using these methods, we can assess and control transmitter release, record cell-type specific activity of neurons, astrocytes and microglia, image blood vessels and analyse synaptic plasticity16 in wildtype mice and disease models. Finally, we seek to translate our findings to human patients with the help collaborators at LMU University Hospital.
To applicants: Please send following initial application documents to LMU-CSC Office before 15th December:
- Resume and Research Motivation Letter
- Certificate of Proficiency in English, equivalent to IELTS Test Academic 6.5 (no module below 6) or TOEFL IBT 95, is required
- Two letters of recommendation directly sent from your current Supervisors/Professors to LMU-CSC Office
Contact LMU-CSC Office: csc.international@lmu.de