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 clinical relevance of discoveries made is assessed through collaborative studies of human patients and brain tissues. The most informative experimental models have been used to identify novel strategies to counteract the development of brain dysfunctions and neurological decline.

Disease Areas

Alzheimer’s Disease
Other Dementias
Epilepsy
Autism Spectrum Disorders

Areas of Expertise

Development of Interdisciplinary Research Programs
Identification and Preclinical Assessment of Novel Therapeutic Strategies
Dissection of Complex Pathogenic Pathways in Experimental Models
Pathobiology of Amyloid Proteins and Tau
Roles of Glial Cells in Health and Disease
Training and Mentorship of Leaders in Disease-Focused Neuroscience
Working in the Mucke lab

Lab Focus

Important brain functions and conditions that impair them
Unraveling disease mechanisms at molecular, cellular, network, and behavioral levels
Identifying novel therapeutic strategies and advancing them toward the clinic

Research Impact

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 they can promote 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 also identified 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.

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 Alzheimer’s disease.

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 treatments. Recent findings from his lab revealed that neural network and immune cell dysfunctions can engage in a vicious disease-promoting cycle that can be disrupted by therapeutic interventions.

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. He also established novel models and 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.

 

Professional Titles

Senior Investigator and Director, Gladstone Institute of Neurological Disease

Director, Gladstone Institute of Neurological Disease

Senior Investigator, Gladstone Institutes

Joseph B. Martin Distinguished Professor of Neuroscience and Professor in the Department of Neurology, UC San Francisco

Bio

Lennart Mucke is the founding director of the Gladstone Institute of Neurological Disease, where he has developed a premier program for research and training in disease-focused neuroscience. He holds joint appointments as the Joseph B. Martin Distinguished Professor of Neuroscience and Professor of Neurology at the University of California, San Francisco (UCSF).

Mucke has unraveled pathophysiological mechanisms of cognitive decline in Alzheimer’s disease and identified unexpected links among Alzheimer’s disease, epilepsy and autism spectrum disorders, as well as related entry points for novel interventions that could be of therapeutic benefit in these as well as other neurological and psychiatric conditions.

Mucke earned his medical degree from the Georg-August University School of Medicine and trained in electrophysiology and neuroanatomy at the Max Planck Institute for Biophysical Chemistry, both in Göttingen, Germany. He trained in internal medicine at the Cleveland Clinic and in neurology at Massachusetts General Hospital and Harvard Medical School. He gained postdoctoral research experience in neuroimmunology, neurovirology and molecular biology at The Scripps Research Institute, where he was subsequently appointed to the faculty. He was recruited to Gladstone and UCSF in 1996.

Widely consulted for his expertise, Mucke has served on the federal government’s National Advisory Council on Aging, the Medical & Scientific Advisory Council of the Alzheimer’s Association, the Senate of the German Center for Neurodegenerative Diseases, and the Scientific Advisory Board of the UK Dementia Research Institute at University College London. He is a co-founder and board member of Cure Network Dolby Acceleration Partners LLC, a Gladstone spin-out company developing new treatments for Alzheimer’s disease.

Deeply committed to training the next generations of scientists, Mucke has mentored over 60 graduate students and postdoctoral scholars. Several of them have assumed major leadership positions in academia or industry, many run their own productive labs, and most continue to make meritorious contributions to disease-focused neuroscience and translational neurobiology.

What keeps you inspired about your research?

“I greatly enjoy helping each of my mentees become the best they can be and I am really excited about the progress the team is making toward blocking important disease mechanisms and advancing our scientific discoveries toward patients in need and people at risk.”

Lennart Mucke, MD

Honors and Awards

2021 Elected member, National Academy of Medicine

2019 Fellow, 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 Named 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 member, Association of American Physicians

2002 MERIT Award, National Institutes of Health

1999 Zenith Award, Alzheimer’s Association

1998 Elected member, American Neurological Association

Publications

Contact

Lennart Mucke
Email
415.734.2504


Lab Members

Rafaella Araujo Goncalves da Silva, PhD
Postdoctoral Scholar
Melanie Das, PhD
Staff Research Scientist II
Phoenix Ding
Research Associate I
Dipankar Dutta, PhD
Staff Research Scientist I
Marcy Fuentes Hernandez
Research Associate I
Thanussh Gnanasegeran
Student Intern
Valeria Grasso, PhD
Affiliate
Elvis Han
Student Intern
Kaitlyn Ho
Research Scientist
Victor Huang, PhD
Postdoctoral Scholar
Sara Knowles, PhD
Postdoctoral Scholar
Letian Li
Student Intern
Syon Mansur
Student Intern
Laura Mitic, PhD
Collaborator
Jenny Moore
Research Associate II
Megumi Mori
Megumi Mori, PhD
Postdoctoral Scholar
Paula Parra Bueno, PhD
Staff Research Scientist III
Cathrine Petersen
Graduate Student
Cathrine Petersen
Graduate Student
Erica Roh
Student Intern
Anika Shah
Student Intern
Eric Shao, PhD
Collaborator
Meena Subbarayan, PhD
Postdoctoral Scholar
Eric Tan
Student Intern
Xin Wang
Research Associate III
Jiaming Wang, MS
Research Associate III
Unekwu Yakubu, PhD
Postdoctoral Scholar
Gui-Qiu Yu, MS
Research Scientist
Allie Zahn
Research Associate II