Li Gan

Last updated
Li Gan
Education
Known forPathogenic tau acetylation; Microglia in neurodegeneration
Scientific career
Fields Neuroscience
Institutions Weill Cornell Medical College
Doctoral advisor Leonard K. Kaczmarek
Other academic advisors
Website labs.gladstone.org/gan/index.html

Li Gan is a neuroscientist and professor at Weill Cornell Medical College. She is known for her discovery of pathogenic tau protein acetylation in tauopathies and mechanisms of microglia dysfunction in neurodegeneration. [1]

Contents

Education and career

Gan attended Peking University from 1986 to 1990 [2] and earned a BS in Physiology. [3] She then attended Yale School of Medicine, [3] where she was advised by Leonard K. Kaczmarek and studied voltage-gated potassium channels in high frequency-firing neurons. [4] Gan received her PhD in Cellular & Molecular Physiology in 1996. [2] Gan conducted postdoctoral studies with Gerald Fischbach at Harvard Medical School and with Lennart Mucke at the Gladstone Institute of Neurological Disease. From 2000 to 2003, she worked at AGY Therapeutics Inc., a biotechnology company based in South San Francisco, CA. [2]

In 2003, Gan joined the Gladstone Institute as a staff research investigator and became an assistant adjunct professor in neurology at the University of California, San Francisco. She was promoted to assistant investigator/assistant professor in residence in 2009, and associate investigator/associate professor in 2011. Gan was promoted to full professor in 2016 and served as associate director of the Gladstone Institute of Neurological Disease from 2017 to 2018 [5] before moving to Weill Cornell Medical College in 2018. [2]

As of 2018, Gan is the Burton P. and Judith B. Resnick Distinguished Professor in Neurodegenerative Disease. She leads the Helen and Robert Appel Alzheimer's Disease Research Institute, where she succeeded Gregory Petsko as director. [1]

Research

The Gan lab studies molecular mechanisms of neurodegeneration in conditions such as Alzheimer's disease (AD) and FTDP-17. Her lab has also developed induced pluripotent stem cell culture models to study human brain cell function. [1]

Gan has elucidated several roles of microglia in aging and disease. Her lab demonstrated that amyloid beta (Aβ) induces NF-κB signaling in microglia, and these microglia are the main mediators of Aβ-induced neuron death. Activation of SIRT1 deacetylase by overexpression or by treatment with resveratrol reduces microglial NF-κB signaling. [6] Her lab has also found that SIRT1 expression in microglia naturally declines with age and causes upregulation of IL-1β, which in turn is correlated with chronological age and cognitive decline in humans. [7] In a 2018 study in mice, the Gan lab demonstrated that haploinsufficiency of TREM2, the strongest immune cell-specific risk factor for AD, impairs microglia motility and increases tau pathology relative to either wildtype or complete knockout mice. [8] Gan is also interested in sex-specific responses of microglia to neurodegeneration. [9]

Gan also studies how mechanisms of proteostasis can contribute to pathogenic protein aggregation. Her lab demonstrated that cathepsin B (CatB) can degrade Aβ, the hallmark protein aggregate in AD. Their study indicated complex roles of cystatin C (CysC); CysC inhibits CatB degradation of Aβ peptides, but CysC itself inhibits the fibrillation of Aβ, which limits the overall rate of Aβ deposition. [10]

In 2010, the Gan lab was first to report that tau acetylation regulates the turnover of pathogenic tau. They found that acetylated tau protein is elevated in early- and moderate-stage tauopathy, and that tau acetylation prevents proteasomal degradation of phosphorylated tau, which is a known mediator of neurodegeneration. Deletion of SIRT1 exacerbated tau acetylation, and inhibition of histone acetyltransferase p300 with the small molecule C646 eliminated pathogenic phospho-tau. [11] Her lab has also demonstrated that acetylated tau is directly pathogenic by destabilizing the axon initial segment. [12]

Awards and honors

Related Research Articles

<span class="mw-page-title-main">Amyloid beta</span> Group of peptides

Amyloid beta denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor protein (APP), which is cleaved by beta secretase and gamma secretase to yield Aβ in a cholesterol-dependent process and substrate presentation. Aβ molecules can aggregate to form flexible soluble oligomers which may exist in several forms. It is now believed that certain misfolded oligomers can induce other Aβ molecules to also take the misfolded oligomeric form, leading to a chain reaction akin to a prion infection. The oligomers are toxic to nerve cells. The other protein implicated in Alzheimer's disease, tau protein, also forms such prion-like misfolded oligomers, and there is some evidence that misfolded Aβ can induce tau to misfold.

<span class="mw-page-title-main">Amyloid plaques</span> Extracellular deposits of the amyloid beta protein

Amyloid plaques are extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of microglia and astrocytes can be associated with amyloid plaques. Some plaques occur in the brain as a result of aging, but large numbers of plaques and neurofibrillary tangles are characteristic features of Alzheimer's disease. Abnormal neurites in amyloid plaques are tortuous, often swollen axons and dendrites. The neurites contain a variety of organelles and cellular debris, and many of them include characteristic paired helical filaments, the ultrastructural component of neurofibrillary tangles. The plaques are highly variable in shape and size; in tissue sections immunostained for Aβ, they comprise a log-normal size distribution curve with an average plaque area of 400-450 square micrometers (µm²). The smallest plaques, which often consist of diffuse deposits of Aβ, are particularly numerous. The apparent size of plaques is influenced by the type of stain used to detect them, and by the plane through which they are sectioned for analysis under the microscope. Plaques form when Aβ misfolds and aggregates into oligomers and longer polymers, the latter of which are characteristic of amyloid. Misfolded and aggregated Aβ is thought to be neurotoxic, especially in its oligomeric state.

<span class="mw-page-title-main">Tauopathy</span> Medical condition

Tauopathy belongs to a class of neurodegenerative diseases involving the aggregation of tau protein into neurofibrillary or gliofibrillary tangles in the human brain. Tangles are formed by hyperphosphorylation of the microtubule protein known as tau, causing the protein to dissociate from microtubules and form insoluble aggregates. The mechanism of tangle formation is not well understood, and whether tangles are a primary cause of Alzheimer's disease or play a peripheral role is unknown.

<span class="mw-page-title-main">Neurodegenerative disease</span> Central nervous system disease

A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic. Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.

The biochemistry of Alzheimer's disease, the most common cause of dementia, is not yet very well understood. Alzheimer's disease (AD) has been identified as a proteopathy: a protein misfolding disease due to the accumulation of abnormally folded amyloid beta (Aβ) protein in the brain. Amyloid beta is a short peptide that is an abnormal proteolytic byproduct of the transmembrane protein amyloid-beta precursor protein (APP), whose function is unclear but thought to be involved in neuronal development. The presenilins are components of proteolytic complex involved in APP processing and degradation.

<span class="mw-page-title-main">Proteinopathy</span> Medical condition

In medicine, proteinopathy, or proteopathy, protein conformational disorder, or protein misfolding disease, is a class of diseases in which certain proteins become structurally abnormal, and thereby disrupt the function of cells, tissues and organs of the body. Often the proteins fail to fold into their normal configuration; in this misfolded state, the proteins can become toxic in some way or they can lose their normal function. The proteinopathies include such diseases as Creutzfeldt–Jakob disease and other prion diseases, Alzheimer's disease, Parkinson's disease, amyloidosis, multiple system atrophy, and a wide range of other disorders. The term proteopathy was first proposed in 2000 by Lary Walker and Harry LeVine.

<span class="mw-page-title-main">TREM2</span> Protein-coding gene in the species Homo sapiens

Triggering receptor expressed on myeloid cells 2(TREM2) is a protein that in humans is encoded by the TREM2 gene. TREM2 is expressed on macrophages, immature monocyte-derived dendritic cells, osteoclasts, and microglia, which are immune cells in the central nervous system. In the liver, TREM2 is expressed by several cell types, including macrophages, that respond to injury. In the intestine, TREM2 is expressed by myeloid-derived dendritic cells and macrophage. TREM2 is overexpressed in many tumor types and has anti-inflammatory activities. It might therefore be a good therapeutic target.

<span class="mw-page-title-main">Alzheimer's disease</span> Progressive neurodegenerative disease

Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens, and is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems with language, disorientation, mood swings, loss of motivation, self-neglect, and behavioral issues. As a person's condition declines, they often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the typical life expectancy following diagnosis is three to nine years.

Early-onset Alzheimer's disease (EOAD), also called younger-onset Alzheimer's disease (YOAD), is Alzheimer's disease diagnosed before the age of 65. It is an uncommon form of Alzheimer's, accounting for only 5–10% of all Alzheimer's cases. About 60% have a positive family history of Alzheimer's and 13% of them are inherited in an autosomal dominant manner. Most cases of early-onset Alzheimer's share the same traits as the "late-onset" form and are not caused by known genetic mutations. Little is understood about how it starts.

<span class="mw-page-title-main">Rudolph E. Tanzi</span> American geneticist

Rudolph Emile 'Rudy' Tanzi a professor of Neurology at Harvard University, vice-chair of neurology, director of the Genetics and Aging Research Unit, and co-director of the Henry and Allison McCance Center for Brain Health at Massachusetts General Hospital (MGH).

Primary age-related tauopathy (PART) is a neuropathological designation introduced in 2014 to describe the neurofibrillary tangles (NFT) that are commonly observed in the brains of normally aged and cognitively impaired individuals that can occur independently of the amyloid plaques of Alzheimer's disease (AD). The term and diagnostic criteria for PART were developed by a large group of neuropathologists, spearheaded by Drs. John F. Crary and Peter T. Nelson. Despite some controversy, the term PART has been widely adopted, with the consensus criteria cited over 1130 times as of April 2023 according to Google Scholar.

<span class="mw-page-title-main">Tara Spires-Jones</span> Professor of Neurodegeneration

Tara Spires-Jones is professor of neurodegeneration and deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh. She is also a group leader in the UK Dementia Research Institute.

The ion channel hypothesis of Alzheimer’s disease (AD), also known as the channel hypothesis or the amyloid beta ion channel hypothesis, is a more recent variant of the amyloid hypothesis of AD, which identifies amyloid beta (Aβ) as the underlying cause of neurotoxicity seen in AD. While the traditional formulation of the amyloid hypothesis pinpoints insoluble, fibrillar aggregates of Aβ as the basis of disruption of calcium ion homeostasis and subsequent apoptosis in AD, the ion channel hypothesis in 1993 introduced the possibility of an ion-channel-forming oligomer of soluble, non-fibrillar Aβ as the cytotoxic species allowing unregulated calcium influx into neurons in AD.

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<span class="mw-page-title-main">Urtė Neniškytė</span> Lithuanian neuroscientist (b. 1983)

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<span class="mw-page-title-main">Bradlee Heckmann</span>

Bradlee L. Heckmann is an American biologist, pharmacologist. Heckmann holds academic appointments as a neuroimmunologist at the Byrd Alzheimer's Center and USF Health Neuroscience Institute and is assistant professor in molecular medicine at the USF Health Morsani College of Medicine. Heckmann's research has been focused on understanding the regulation of inflammatory and metabolic processes in the central nervous system, with particular emphasis on neurodegenerative diseases including Alzheimer's disease and the role of the autophagy machinery in this setting.

<span class="mw-page-title-main">Katerina Akassoglou</span> Greek neuroimmunologist

Katerina Akassoglou is a neuroimmunologist who is a Senior Investigator and Director of In Vivo Imaging Research at the Gladstone Institutes. Akassoglou holds faculty positions as a Professor of Neurology at the University of California, San Francisco. Akassoglou has pioneered investigations of blood-brain barrier integrity and development of neurological diseases. She found that compromised blood-brain barrier integrity leads to fibrinogen leakage into the brain inducing neurodegeneration. Akassoglou is internationally recognized for her scientific discoveries.

Lary Walker is an American neuroscientist and researcher at Emory University in Atlanta, Georgia. He is Associate Director of the Goizueta Alzheimer's Disease Research Center at Emory, and he is known for his research on the role of abnormal proteins in the causation of Alzheimer’s disease.

<span class="mw-page-title-main">David M. Holtzman</span> Medical researcher

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References

  1. 1 2 3 "Neuroscientist Dr. Li Gan to Lead Appel Alzheimer's Research Institute". Weill Cornell Medicine. July 2, 2018. Retrieved 2021-11-11.
  2. 1 2 3 4 "Li Gan". ORCiD. Retrieved 2021-11-11.
  3. 1 2 "Lab members | gan lab". Gladstone Institutes. Retrieved 2021-11-11.
  4. ↑ Gan L, Perney TM, Kaczmarek LK (1996). "Cloning and characterization of the promoter for a potassium channel expressed in high frequency firing neurons". J Biol Chem. 271 (10): 5859–65. doi: 10.1074/jbc.271.10.5859 . PMID   8621457.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ↑ Howard, Gary C. (March 30, 2017). "Gladstone Names New Associate Director of Neuroscience". Gladstone Institutes. Retrieved 2021-11-11.
  6. ↑ Chen J, Zhou Y, Mueller-Steiner S, Chen LF, Kwon H, Yi S; et al. (2005). "SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling". J Biol Chem. 280 (48): 40364–74. doi: 10.1074/jbc.M509329200 . PMID   16183991.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ↑ Cho SH, Chen JA, Sayed F, Ward ME, Gao F, Nguyen TA; et al. (2015). "SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1β". J Neurosci. 35 (2): 807–18. doi:10.1523/JNEUROSCI.2939-14.2015. PMC   4293425 . PMID   25589773.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ↑ Sayed FA, Telpoukhovskaia M, Kodama L, Li Y, Zhou Y, Le D; et al. (2018). "Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy". Proc Natl Acad Sci U S A. 115 (40): 10172–10177. Bibcode:2018PNAS..11510172S. doi: 10.1073/pnas.1811411115 . PMC   6176614 . PMID   30232263.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ↑ Kodama L, Gan L (2019). "Do Microglial Sex Differences Contribute to Sex Differences in Neurodegenerative Diseases?". Trends Mol Med. 25 (9): 741–749. doi:10.1016/j.molmed.2019.05.001. PMC   7338035 . PMID   31171460.
  10. ↑ Sun B, Zhou Y, Halabisky B, Lo I, Cho SH, Mueller-Steiner S; et al. (2008). "Cystatin C-cathepsin B axis regulates amyloid beta levels and associated neuronal deficits in an animal model of Alzheimer's disease". Neuron. 60 (2): 247–57. doi:10.1016/j.neuron.2008.10.001. PMC   2755563 . PMID   18957217.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ↑ Min SW, Cho SH, Zhou Y, Schroeder S, Haroutunian V, Seeley WW; et al. (2010). "Acetylation of tau inhibits its degradation and contributes to tauopathy". Neuron. 67 (6): 953–66. doi:10.1016/j.neuron.2010.08.044. PMC   3035103 . PMID   20869593.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ↑ Sohn PD, Tracy TE, Son HI, Zhou Y, Leite RE, Miller BL; et al. (2016). "Acetylated tau destabilizes the cytoskeleton in the axon initial segment and is mislocalized to the somatodendritic compartment". Mol Neurodegener. 11 (1): 47. doi: 10.1186/s13024-016-0109-0 . PMC   4928318 . PMID   27356871.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ↑ Gan, Li (July 1, 2015). "Inge Grundke-Iqbal award for Alzheimer's research: Progranulin protects against amyloid b deposition and toxicity in Alzheimer's disease mouse models". Alzheimer's & Dementia. 11 (7): 216. doi:10.1016/j.jalz.2015.07.235. S2CID   54264047.
  14. ↑ "Glenn Award for Research in Biological Mechanisms of Aging". Glenn Foundation for Medical Research. Retrieved 2021-11-11.
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