About

Virginia Man-Yee Lee, Ph.D., is the John H. Ware 3rd Endowed Professor in Alzheimer's Research at the University of Pennsylvania. She is the director of the Center for Neurodegenerative Disease Research in the Department of Pathology and Laboratory Medicine. Her research focuses on the biology of tau, synucleins, TDP-43, and amyloid beta precursor proteins (APPs) in health and disease. Dr. Lee's work demonstrates that proteins such as tau, alpha-synuclein, and TDP-43 form unique brain aggregates in neurodegenerative diseases, providing critical evidence that the aggregation of brain proteins is a common mechanistic theme across disorders including Alzheimer's disease, Parkinson's disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis. Her studies have implicated abnormal protein aggregation in mechanisms that compromise neuronal viability, opening new avenues for drug discovery and treatment development for these neurodegenerative disorders.

Research topics

• Pathology
• Biology
• Medicine
• Neuroscience
• Cell biology
• Immunology
• Biochemistry
• Physics
• Psychology

Selected publications

• An HDAC6-dependent surveillance mechanism suppresses tau-mediated neurodegeneration and cognitive decline

  Nature Communications · 2020 · 101 citations

  • Neuroscience
  • Biology
  • Cell biology

  Tauopathies including Alzheimer's disease (AD) are marked by the accumulation of aberrantly modified tau proteins. Acetylated tau, in particular, has recently been implicated in neurodegeneration and cognitive decline. HDAC6 reversibly regulates tau acetylation, but its role in tauopathy progression remains unclear. Here, we identified an HDAC6-chaperone complex that targets aberrantly modified tau. HDAC6 not only deacetylates tau but also suppresses tau hyperphosphorylation within the microtubule-binding region. In neurons and human AD brain, HDAC6 becomes co-aggregated within focal tau swellings and human AD neuritic plaques. Using mass spectrometry, we identify a novel HDAC6-regulated tau acetylation site as a disease specific marker for 3R/4R and 3R tauopathies, supporting uniquely modified tau species in different neurodegenerative disorders. Tau transgenic mice lacking HDAC6 show reduced survival characterized by accelerated tau pathology and cognitive decline. We propose that a HDAC6-dependent surveillance mechanism suppresses toxic tau accumulation, which may protect against the progression of AD and related tauopathies.

  DOI

• Distribution patterns of tau pathology in progressive supranuclear palsy

  Acta Neuropathologica · 2020 · 459 citations

  • Neuroscience
  • Pathology
  • Biology

  Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PSP pathology. We evaluated heat maps and distribution patterns of neuronal, astroglial, and oligodendroglial tau pathologies and their combinations in different clinical subtypes of PSP in postmortem brains. We used conditional probability and logistic regression to model the sequential distribution of tau pathologies across different brain regions. Tau pathology uniformly predominates in the neurons of the pallido-nigro-luysian axis in different clinical subtypes. However, clinical subtypes are distinguished not only by total tau load but rather cell-type (neuronal versus glial) specific vulnerability patterns of brain regions suggesting distinct dynamics or circuit-specific segregation of propagation of tau pathologies. For Richardson syndrome (n = 81) we recognize six sequential steps of involvement of brain regions by the combination of cellular tau pathologies. This is translated to six stages for the practical neuropathological diagnosis by the evaluation of the subthalamic nucleus, globus pallidus, striatum, cerebellum with dentate nucleus, and frontal and occipital cortices. This system can be applied to further clinical subtypes by emphasizing whether they show caudal (cerebellum/dentate nucleus) or rostral (cortical) predominant, or both types of pattern. Defining cell-specific stages of tau pathology helps to identify preclinical or early-stage cases for the better understanding of early pathogenic events, has implications for understanding the clinical subtype-specific dynamics of disease-propagation, and informs tau-neuroimaging on distribution patterns.

  DOI

• Spread of pathological tau proteins through communicating neurons in human Alzheimer’s disease

  Nature Communications · 2020 · 532 citations

  • Neuroscience
  • Biology
  • Psychology

  Tau is a hallmark pathology of Alzheimer's disease, and animal models have suggested that tau spreads from cell to cell through neuronal connections, facilitated by β-amyloid (Aβ). We test this hypothesis in humans using an epidemic spreading model (ESM) to simulate tau spread, and compare these simulations to observed patterns measured using tau-PET in 312 individuals along Alzheimer's disease continuum. Up to 70% of the variance in the overall spatial pattern of tau can be explained by our model. Surprisingly, the ESM predicts the spatial patterns of tau irrespective of whether brain Aβ is present, but regions with greater Aβ burden show greater tau than predicted by connectivity patterns, suggesting a role of Aβ in accelerating tau spread. Altogether, our results provide evidence in humans that tau spreads through neuronal communication pathways even in normal aging, and that this process is accelerated by the presence of brain Aβ.

  DOI

• Nasal vaccine delivery attenuates brain pathology and cognitive impairment in tauopathy model mice

  npj Vaccines · 2020 · 21 citations

  • Neuroscience
  • Pathology
  • Medicine

  Pathological aggregates of tau proteins accumulate in the brains of neurodegenerative tauopathies including Alzheimer's disease and frontotemporal lobar degeneration (FTLD-tau). Although immunotherapies of these disorders against tau are emerging, it is unknown whether nasal delivery, which offers many benefits over traditional approaches to vaccine administration, is effective or not for tauopathy. Here, we developed vaccination against a secreted form of pathological tau linked to FTLD-tau using a Sendai virus (SeV) vector infectious to host nasal mucosa, a key part of the immune system. Tau vaccines given as nasal drops induced tissue tau-immunoreactive antibody production and ameliorated cognitive impairment in FTLD-tau model mice. In vivo imaging and postmortem neuropathological assays demonstrated the suppression of phosphorylated tau accumulation, neurotoxic gliosis, and neuronal loss in the hippocampus of immunized mice. These findings suggest that nasal vaccine delivery may provide a therapeutic opportunity for a broad range of populations with human tauopathy.

  PublisherOA PDFDOI

• Protein transmission in neurodegenerative disease

  Nature Reviews Neurology · 2020 · 599 citations

  Senior authorCorresponding
  • Medicine
  • Neuroscience
  • Cell biology
  DOI

• Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease

  Journal of Clinical Investigation · 2020 · 596 citations

  • Biology
  • Immunology
  • Cell biology

  Type I interferon (IFN) is a key cytokine that curbs viral infection and cell malignancy. Previously, we demonstrated a potent IFN immunogenicity of nucleic acid-containing (NA-containing) amyloid fibrils in the periphery. Here, we investigated whether IFN is associated with β-amyloidosis inside the brain and contributes to neuropathology. An IFN-stimulated gene (ISG) signature was detected in the brains of multiple murine Alzheimer disease (AD) models, a phenomenon also observed in WT mouse brain challenged with generic NA-containing amyloid fibrils. In vitro, microglia innately responded to NA-containing amyloid fibrils. In AD models, activated ISG-expressing microglia exclusively surrounded NA+ amyloid β plaques, which accumulated in an age-dependent manner. Brain administration of rIFN-β resulted in microglial activation and complement C3-dependent synapse elimination in vivo. Conversely, selective IFN receptor blockade effectively diminished the ongoing microgliosis and synapse loss in AD models. Moreover, we detected activated ISG-expressing microglia enveloping NA-containing neuritic plaques in postmortem brains of patients with AD. Gene expression interrogation revealed that IFN pathway was grossly upregulated in clinical AD and significantly correlated with disease severity and complement activation. Therefore, IFN constitutes a pivotal element within the neuroinflammatory network of AD and critically contributes to neuropathogenic processes.

  DOI

Recent grants

• NIH Grant P01AG014382

  NIH · $13.4M · 2009

• NIH Grant R01AG010210

  NIH · $2.0M · 2003

• NIH Grant P01AG032953

  NIH · $5.8M · 2016

• NIH Grant P50NS053488

  NIH · $33.7M · 2018

• NIH Grant P01AG009215

  NIH · $16.3M · 2011

Frequent coauthors

• John Q. Trojanowski

  University of Pennsylvania

  1709 shared

• Vivianna M. Van Deerlin

  University of Pennsylvania

  285 shared

• Murray Grossman

  257 shared

• Leo McCluskey

  University Hospital of Wales

  204 shared

• Lauren Elman

  University of Pennsylvania

  194 shared

• Sharon X. Xie

  187 shared

• Linda K. Kwong

  Institute on Aging

  183 shared

• Steven E. Arnold

  Harvard University

  179 shared

Education

• B.A.

  Royal Academy of Music, London, England

  1964

• Other, Chemistry

  Univ. of London, England

  1967

• Other, Biochemistry

  Univ. of London, England

  1968

• Ph.D., Biochemistry

  University of California at San Francisco

  1973

• Other

  Wharton School, University of Pennsylvania, Philadelphia

  1984

Awards & honors

• John H. Ware 3rd Endowed Professor in Alzheimer's Research

Similar researchers at University of Pennsylvania

• John Q. Trojanowskih-296
• Craig B. Thompsonh-277
• Daniel J Raderh-236
• Carl H. Juneh-218
• M. Celeste Simonh-185