Lennart Mucke’s lab focuses on how major neurological and psychiatric conditions cause cognitive deficits, behavioral abnormalities, and other disabling symptoms, with an emphasis on dementias, epilepsy, and autism. The group uses mouse models and brain cell cultures to study disease-causing factors and pathways at molecular, cellular, network, and behavioral levels. Such models are also used to identify and validate novel entry points for therapeutic interventions. The relevance of the models is assessed through comparative studies of human patients and postmortem tissues. The most informative models have been used to identify novel strategies to counteract the development of brain dysfunctions and neurological decline.
Areas of Expertise
Genetic variants of the amyloid precursor protein (APP), microtubule-associated protein tau, and apolipoprotein E (apoE) can cause or increase the risk of Alzheimer’s disease. Abnormal accumulations of APP-derived amyloid-β (Aβ) peptides and of tau form amyloid plaques and neurofibrillary tangles, respectively, two pathological hallmarks of the disease. Findings by the Mucke Lab revealed that APP/Aβ, tau, and apoE4 can cause neuronal deficits independent of plaques and tangles and that APP/Aβ causes not only synaptic depression, but also neural network hyperexcitability. The group further showed that reducing neuronal tau levels prevents network hyperexcitability of diverse causes and is well tolerated, revealing a novel role for tau in the regulation of neuronal activity and challenging the long-standing notion that tau aggregation causes neurodegeneration through loss of tau functions.
These discoveries established unexpected links among Alzheimer’s disease, epilepsy, and autism, and paved the path toward the development of tau-lowering therapeutics, which is now pursued in academic laboratories and pharmaceutical companies around the world. Mucke’s long-standing research efforts in neuroimmunology have highlighted the importance of differentiating between beneficial and detrimental activities of non-neuronal brain cells. such as astrocytes and microglia, particularly in the design of immune-modulatory therapeutics.
In animal models of Alzheimer’s disease, Mucke and his team showed that suppression of nonconvulsive epileptiform activity reverses synaptic and cognitive deficits. Follow-on studies with clinical collaborators led to the discoveries that a substantial proportion of Alzheimer’s patients have such abnormal brain activity and that its presence predicts faster cognitive decline. These insights provided critical guidance for the design of clinical trials aimed at reversing network dysfunction in early stages of Alzheimer’s disease.
Overall, Mucke’s contributions have advanced the field from its traditional focus on morphological changes toward an understanding of Alzheimer’s disease at the synaptic and neural network level and have identified novel therapeutic strategies in a field in desperate need of them. In addition, he has developed novel strategies to expedite the translation of scientific discoveries into better treatments for brain diseases that are frequent, devastating, and costly to populations around the world.
Director, Gladstone Institute of Neurological Disease
Senior Investigator, Gladstone Institutes
Joseph B. Martin Distinguished Professor of Neuroscience and Professor of Neurology, UC San Francisco
Lennart Mucke is the director of the Gladstone Institute of Neurological Disease, and a senior investigator at Gladstone. He is also the Joseph B. Martin Distinguished Professor of Neuroscience and a professor of neurology at UC San Francisco (UCSF). He has joint appointments in UCSF’s Neuroscience, Biomedical Sciences, and Medical Scientist (MD/PhD) Graduate Training Programs.
Mucke is a graduate of the Georg-August University and the Max Planck Institute for Biophysical Chemistry (Neurobiology) in Göttingen, Germany. He trained in internal medicine at the Cleveland Clinic, in neurology at Massachusetts General Hospital and Harvard Medical School, and in neuroimmunology and neurovirology at The Scripps Research Institute, where he was subsequently appointed to the faculty. Mucke was recruited to Gladstone Institutes in 1996.
How Did You Get Your Start in Science?
“I developed a great interest in psychiatry, neurology, and neuroscience in high school and, to this day, can’t think of anything more fascinating and rewarding than to discover how the brain works and how to preserve the fragile structures that harbor the very essence of who we are.”
Honors and Awards
2021 Elected Member of the National Academy of Medicine
2019 Fellow of the German Center for Neurodegenerative Diseases (DZNE)
2013 MetLife Award for Medical Research in Alzheimer’s Disease, MetLife Foundation
2013 American Pacesetter Award, ARCS Foundation
2013 J. Elliott Royer Award for Excellence in Academic Neurology, UC San Francisco
2012 Khalid Iqbal Lifetime Achievement Award in Recognition of Outstanding Research, Alzheimer’s Association
2012 Honorary Citizen of New Orleans
2011 Chancellor’s Award in Neurosciences, Louisiana State University
2010 Potamkin Prize for Research in Pick’s, Alzheimer’s, and Related Diseases, American Academy of Neurology
2007 Award for Excellence in Direct Teaching and/or Excellence in Mentoring and Advising, Haile T. Debas Academy of Medical Educators
2006 Arthur Cherkin Memorial Award, UCLA
2003 Promising Investigator Award, MetLife Foundation
2003 Elected to the Association of American Physicians
1999 Zenith Award, Alzheimer’s Association
1998 Elected to the American Neurological Association
Administrative Program Manager