Project Details
Projekt
Spatiotemporally resolved microglial diversity and reciprocal interaction with the noradrenergic system in Alzheimer’s disease
Applicants
Dr. Lars Paeger; Dr. Felix Strübing
Subject Area
Experimental Models for the Understanding of Nervous System Diseases
Human Genetics
Human Genetics
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 559330405
Microglia are also known as the main "garbage disposal system" present in the brain, but this denomination disregards their important function in development and health. As such, their roles are not limited to the removal of debris; for example, they play a major part in synaptic plasticity, a molecular phenomenon underlying the brain’s ability to constantly rewire ist circuits throughout the span of one’s life. Once this ability is lost, cognitive function declines, constituting advanced symptoms of dementias such as Alzheimer’s Disease (AD). It is now well-known that the molecular processes leading up to AD predate cognitive decline at least by a decade - therefore, earliest intervention is of utmost importance, knowing that the disease course can only be slowed with the currently available therapies. One of the earliest prodromal signs of AD is loss of smell (hyposmia). In our own previous work, we were able to show in a ß-amyloid mouse model of AD that microglia in the olfactory bulb, the brain region responsible for the sense of smell, remove nerve fibers releasing noradrenaline (aka norepinephrine), a neurotransmitter most well-known for ist attention- and wakefulness-promoting effects and modulation of olfaction. Loss of noradrenaline is a physiological phenomenon associated with aging, but accelerated in AD, where the accumulation of ß-Amyloid drives microglia to lose their balance and preferentially digest more synapses. This was paralleled by an early microgliosis in the olfactory bulb of prodromal AD patients, who showed olfactory deficits. Similarly, noradrenergic innervation in olfactory bulb post-mortem tissue from prodromal AD patients was drastically reduced. However, hyposmia does not have as drastic socioeconomic consequences as later symptoms occurring in AD (i.e. cognitive and functional decline), constituting the impetus for this proposal. Herein, we want to extend on our previous data to investigate the relationship of noradrenaline and microglia dynamics in cortex and hippocampus, two brain regions associated with memory loss and functional decline. The applicants’ expertise is ideally suited to perform these experiments: we will make use of state-of-the-art mouse models, high-throughput sequencing, including spatiotemporally resolved transcriptomic assays, pharmacologic and opto-/chemogenetic modulation, in vivo imaging methods, as well as sophisticated bioinformatic analysis pipelines. Our results aim to improve the understanding of noradrenaline’s effect on microglia in physiology and pathology, and serve as a potential basis for an improved therapy regimen in which the modulation of noradrenaline in specific brain areas might lead to a superior health outcome in patients at risk.
DFG Programme
Priority Programmes
