Lennart Mucke, MD
Neurobiology of Diseases Affecting Cognitive Function
Areas of investigation
We study processes that result in memory loss and other major neurological deficits, with an emphasis on Alzheimer's disease and related neurodegenerative disorders. Our long-term goal is to advance the understanding of the healthy and the diseased central nervous system to a point where rational strategies can be developed for the prevention and cure of these conditions.
Significance
Molecules similar to those involved in neurodegenerative diseases are highly expressed in the nervous system of diverse species and appear to function in learning, synaptic plasticity, and regeneration. We are particularly curious about the roles of amyloid precursor proteins and apolipoprotein E in Alzheimer's disease, and -synuclein in Parkinson's disease. Alzheimer's and Parkinson's disease are the most frequent neurodegenerative disorders. They erode people's ability to think and control their movements, two of the most critical and intriguing functions of the central nervous system. Both conditions are on the rise and neither can be prevented or cured. These facts underline the significance and urgency of our research efforts.
Approaches
We use transgenic mouse models and neural cultures to study potential pathogenic factors and pathways at the molecular, cellular, network, and behavioral level. Mouse models are also used to develop and evaluate novel treatment strategies. Their relevance is assessed through comparative studies of human postmortem tissues and collaborations with clinical programs.
Contributions
In Alzheimer-related transgenic models, we discovered that amyloid peptides (A ) can damage synapses and disrupt neural memory circuits independent of their deposition into the visible amyloid plaques that form in Alzheimer brains. The plaque-independent toxicity of A was inhibited by apolipoprotein E3, but not E4, which may relate to the differential effects of these molecules on Alzheimer risk and age of onset. Pathogenic interactions between A and -synuclein worsened cognitive and motor deficits in doubly transgenic mice, a finding of potential relevance to the frequent overlap between Alzheimer's and Parkinson's disease.
Current Projects
Questions Addressed in Ongoing Studies
- Are Alzheimer-related neurological deficits due primarily to neuronal death or dysfunction?
- What can the selective vulnerability of specific neuronal populations to different neurodegenerative disorders teach us about the uniqueness of the affected cells and the pathogenic cascades involved?
- How do amyloid peptides (A ) and amyloid precursor proteins affect synaptic function and neuronal survival?
- Which types of A assemblies are the most toxic and why?
- Is it possible to unravel and block the pathogenic cascades they trigger?
- Can their formation and removal be modulated therapeutically?
Lab Website
Academic community service and committee membership:
Weill Neuroscience Cabinet, Weill Institute for Neurosciences, Neurology Leadership Committee, Department of Neurology