Lennart Mucke, MD

Professor
Joseph B. Martin Distinguished Professor of Neuroscience
Director and Senior Investigator, Gladstone Institute of Neurological Disease
Department of Neurology
+1 415 734-2504
Research Description: 

Areas of investigation
We study processes that result in memory loss and other major neurological deficits, with an emphasis on Alzheimerís disease (AD) 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 AD, and a-synuclein in Parkinsonís disease (PD). AD and PD are the most frequent neurodegenerative disorders. They erode peopleís 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 humans and postmortem tissues in collaboration with clinical programs.

Contributions
In AD-related transgenic models, we discovered that amyloid-ß peptides (Aß) can damage synapses and disrupt neural memory circuits independent of their deposition into the visible amyloid plaques that form in AD brains. The plaque-independent toxicity of Aß was inhibited by apolipoprotein E3, but not E4, which may relate to the differential effects of these molecules on AD risk and age of onset. Pathogenic interactions between Aß and a-synuclein worsened cognitive and motor deficits in doubly transgenic mice, a finding of potential relevance to the frequent overlap between AD and PD. Most recently, we discovered that neural network activity in AD-related mouse models fluctuates between abnormal excitation (epilepsy-like) and abnormal inhibition. Remarkably, reducing the protein tau effectively prevented these alterations as well as Aß-induced cognitive deficits. Ongoing studies aim to determine whether such network dysfunction also contributes to cognitive deficits in AD.

Some questions addressed in ongoing studies

How does Aß affect synaptic function and neuronal survival?
How does tau reduction make the brain resistant against Aß-induced deficits?
Can the beneficial effect of tau reduction be exploited therapeutically?
Which drugs can block the aberrant network activity that Aß triggers?
Will these drugs also normalize cognitive functions and prevent neurological decline in AD?
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?

Primary Thematic Area: 
Neurobiology
Secondary Thematic Area: 
Tissue / Organ Biology & Endocrinology
Research Summary: 
Neurobiology of Alzheimer’s Disease and Other Cognitive Disorders

Websites

Publications: 

Tau Reduction Prevents Key Features of Autism in Mouse Models.

Neuron

Tai C, Chang CW, Yu GQ, Lopez I, Yu X, Wang X, Guo W, Mucke L

Early neuronal accumulation of DNA double strand breaks in Alzheimer's disease.

Acta neuropathologica communications

Shanbhag NM, Evans MD, Mao W, Nana AL, Seeley WW, Adame A, Rissman RA, Masliah E, Mucke L

Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer's Disease Model.

Neuron

Merlini M, Rafalski VA, Rios Coronado PE, Gill TM, Ellisman M, Muthukumar G, Subramanian KS, Ryu JK, Syme CA, Davalos D, Seeley WW, Mucke L, Nelson RB, Akassoglou K

Klotho controls the brain-immune system interface in the choroid plexus.

Proceedings of the National Academy of Sciences of the United States of America

Zhu L, Stein LR, Kim D, Ho K, Yu GQ, Zhan L, Larsson TE, Mucke L

Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration.

Nature immunology

Ryu JK, Rafalski VA, Meyer-Franke A, Adams RA, Poda SB, Rios Coronado PE, Pedersen LØ, Menon V, Baeten KM, Sikorski SL, Bedard C, Hanspers K, Bardehle S, Mendiola AS, Davalos D, Machado MR, Chan JP, Plastira I, Petersen MA, Pfaff SJ, Ang KK, Hallenbeck KK, Syme C, Hakozaki H, Ellisman MH, Swanson RA, Zamvil SS, Arkin MR, Zorn SH, Pico AR, Mucke L, Freedman SB, Stavenhagen JB, Nelson RB, Akassoglou K