Dena Dubal

Last updated
Dena Bharat Dubal
Alma mater University of California, Berkeley (BSc)
University of Kentucky (MD)
Scientific career
Institutions University of California, San Francisco
Thesis Estradiol protects the brain against stroke injury : potential mechanisms of action  (2001)
Website Dubal Laboratory

Dena Dubal is the David A. Coulter Endowed Chair in Ageing and Neurodegenerative Disease at University of California, San Francisco. Dubal has demonstrated that the hormone Klotho can enhance cognition and protect the brain from neurodegenerative decline.

Contents

Early life and education

Dubal is from Houston. She attended Episcopal High School and graduated in 1992. [1] She was an undergraduate student at the University of California, Berkeley, where she studied neuroscience with a minor in anthropology. [2] During her undergraduate physiology classes, she recognised that the process of ageing still presented many mysteries to the scientific community. [2] After earning her bachelor's degree, Dubal studied medicine at the University of Kentucky College of Medicine. [3] She worked with Phyllis Wise on the impact of hormones on brain injuries caused by stroke. [4] She was a neurological resident at the University of California, San Francisco, where she was elected Chief Resident and continued to research ageing.

Research and career

Dubal studies the molecular mechanisms of resilience and how these are impacted by neurodegenerative diseases. [4] [5] She holds the David A. Coulter Endowed Chair in Ageing and Neurodegenerative Disease at University of California, San Francisco, and practises as a neurologist in San Francisco. [6] In 2011, she started working on the Klotho hormone. [7] [8] At the time it was known that mice who were bred to make extra Klotho had lives that were 30% longer than those without it. [7] Dubal demonstrated that mice with Alzheimer's disease with extra Klotho were protected from dementia. [9] [10] [11] She went on to show that the brains of healthy mice with extra Klotho were not only protected from neurodegeneration, but their cognitive abilities were enhanced. [12] [13] [14] It has since been shown that Klotho can act to protect against Parkinson's and multiple sclerosis. [7] The mechanisms that underpin Klotho's enhancement of cognitive ability are still unknown. [7]

Alongside working on mouse models, in 2019, Dubal was the first to show that Klotho may protect people from Alzheimer's disease. She demonstrated this by monitoring for the well-known Alzheimer's disease risk factors Apolipoprotein E (APOE) e4. [15] Dubal revealed that patients with the genetic variant APOE e4 have biomarkers of Alzheimer's disease, even before experiencing symptoms, whilst patients with APOE e4 and Klotho do not have these biomarkers. [15]

Dubal has identified a biological mechanism – an epigenetic change on the X chromosome – that may give rise to why women live longer. [2] [16] [17] She has shown that female mice with a particular pattern of sex hormones during their ovarian cycle are more likely to suffer from cognitive decline. [18]

Awards and honours

Selected publications

Related Research Articles

Vascular dementia (VaD) is dementia caused by problems in the supply of blood to the brain, typically a series of minor strokes, leading to worsening cognitive abilities, the decline occurring piecemeal. The term refers to a syndrome consisting of a complex interaction of cerebrovascular disease and risk factors that lead to changes in brain structures due to strokes and lesions, resulting in changes in cognition. The temporal relationship between a stroke and cognitive deficits is needed to make the diagnosis.

Aging of the brain is a process of transformation of the brain in older age, including changes all individuals experience and those of illness. Usually this refers to humans.

<span class="mw-page-title-main">Tau protein</span> Group of six protein isoforms produced from the MAPT gene

The tau proteins are a group of six highly soluble protein isoforms produced by alternative splicing from the gene MAPT. They have roles primarily in maintaining the stability of microtubules in axons and are abundant in the neurons of the central nervous system (CNS), where the cerebral cortex has the highest abundance. They are less common elsewhere but are also expressed at very low levels in CNS astrocytes and oligodendrocytes.

Semantic dementia (SD), also known as semantic variant primary progressive aphasia (svPPA), is a progressive neurodegenerative disorder characterized by loss of semantic memory in both the verbal and non-verbal domains. However, the most common presenting symptoms are in the verbal domain. Semantic dementia is a disorder of semantic memory that causes patients to lose the ability to match words or images to their meanings. However, it is fairly rare for patients with semantic dementia to develop category specific impairments, though there have been documented cases of it occurring. Typically, a more generalized semantic impairment results from dimmed semantic representations in the brain.

<span class="mw-page-title-main">Klotho (biology)</span> Human enzyme

Klotho is an enzyme that in humans is encoded by the KL gene. The three subfamilies of klotho are α-klotho, β-klotho, and γ-klotho. α-klotho activates FGF23, and β-klotho activates FGF19 and FGF21. When the subfamily is not specified, the word "klotho" typically refers to the α-klotho subfamily, because α-klotho was discovered before the other members.

<span class="mw-page-title-main">Apolipoprotein E</span> Cholesterol-transporting protein most notably implicated in Alzheimers disease

Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in the Alzheimer's disease and cardiovascular diseases. It is encoded in humans by the gene APOE.

<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, 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.

<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. It 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.

Alzheimer's Disease Neuroimaging Initiative (ADNI) is a multisite study that aims to improve clinical trials for the prevention and treatment of Alzheimer's disease (AD). This cooperative study combines expertise and funding from the private and public sector to study subjects with AD, as well as those who may develop AD and controls with no signs of cognitive impairment. Researchers at 63 sites in the US and Canada track the progression of AD in the human brain with neuroimaging, biochemical, and genetic biological markers. This knowledge helps to find better clinical trials for the prevention and treatment of AD. ADNI has made a global impact, firstly by developing a set of standardized protocols to allow the comparison of results from multiple centers, and secondly by its data-sharing policy which makes available all at the data without embargo to qualified researchers worldwide. To date, over 1000 scientific publications have used ADNI data. A number of other initiatives related to AD and other diseases have been designed and implemented using ADNI as a model. ADNI has been running since 2004 and is currently funded until 2021.

<span class="mw-page-title-main">Carol A. Barnes</span> American neuroscientist

Carol A. Barnes, Ph.D., is a neuroscientist and a Regents' Professor of psychology at the University of Arizona. Since 2006, she has been the Evelyn F. McKnight Chair for Learning and Memory in Aging and is director of the Evelyn F. McKnight Brain Institute. Barnes has been president of the Society for Neuroscience and is a Fellow of the American Association for the Advancement of Science, and foreign member of the Royal Norwegian Society of Sciences and Letters. She was elected to the National Academy of Sciences in 2018.

The neuroscience of aging is the study of the changes in the nervous system that occur with ageing. Aging is associated with many changes in the central nervous system, such as mild atrophy of the cortex that is considered non-pathological. Aging is also associated with many neurological and neurodegenerative disease such as amyotrophic lateral sclerosis, dementia, mild cognitive impairment, Parkinson's disease, and Creutzfeldt–Jakob disease.

Li-Huei Tsai is a neuroscientist and the director of the Picower Institute for Learning and Memory in the Department of Brain and Cognitive Sciences at the Massachusetts Institute of Technology.

Benjamin Wolozin is an American pharmacologist and neurologist currently at Boston University School of Medicine and an Elected Fellow of the American Association for the Advancement of Science. Benjamin Wolozin, M.D., Ph.D. received his B.A. from Wesleyan University and his M.D., Ph.D. from the Albert Einstein College of Medicine. He is currently a professor of Pharmacology, Neurology and the Program in Neuroscience at Boston University School of Medicine. He is also co-founder and Chief Scientific Officer (CSO) of Aquinnah Pharmaceuticals Inc., a biotechnology company developing novel therapeutics to treat Alzheimer's disease and Amyotrophic Lateral Sclerosis.

<span class="mw-page-title-main">Phenserine</span> Chemical compound

Phenserine is a synthetic drug which has been investigated as a medication to treat Alzheimer's disease (AD), as the drug exhibits neuroprotective and neurotrophic effects.

<span class="mw-page-title-main">Marion Buckwalter</span> American neurologist

Marion Buckwalter is an American neurologist and neuroscientist and Professor of Neurology and Neurosurgery at the Stanford University Medical Center. Buckwalter studies how inflammatory responses affect brain recovery after injury or insult, with a specific emphasis on the neuroimmune and glial cell response after stroke.

Carmela R. Abraham is an American neuroscientist who focuses on the study of Alzheimer’s disease.

Rachelle Smith Doody is an American neurologist and neuroscientist. She is known for her work on late stage development of drugs for Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and other neurodegenerative disorders.

Martha Clare Morris was an American nutritional epidemiologist who studied the link between diet and Alzheimer's disease. She led a team of researchers at the Rush University Medical Center to develop the MIND diet.

Alzheimer's disease (AD) in the Hispanic/Latino population is becoming a topic of interest in AD research as Hispanics and Latinos are disproportionately affected by Alzheimer's Disease and underrepresented in clinical research. AD is a neurodegenerative disease, characterized by the presence of amyloid-beta plaques and neurofibrillary tangles, that causes memory loss and cognitive decline in its patients. However, pathology and symptoms have been shown to manifest differently in Hispanic/Latinos, as different neuroinflammatory markers are expressed and cognitive decline is more pronounced. Additionally, there is a large genetic component of AD, with mutations in the amyloid precursor protein (APP), Apolipoprotein E APOE), presenilin 1 (PSEN1), bridging Integrator 1 (BIN1), SORL1, and Clusterin (CLU) genes increasing one's risk to develop the condition. However, research has shown these high-risk genes have a different effect on Hispanics and Latinos then they do in other racial and ethnic groups. Additionally, this population experiences higher rates of comorbidities, that increase their risk of developing AD. Hispanics and Latinos also face socioeconomic and cultural factors, such as low income and a language barrier, that affect their ability to engage in clinical trials and receive proper care.

Alzheimer's disease (AD) in African Americans is becoming a rising topic of interest in AD care, support, and scientific research, as African Americans are disproportionately affected by AD. Recent research on AD has shown that there are clear disparities in the disease among racial groups, with higher prevalence and incidence in African Americans than the overall average. Pathologies for Alzheimer’s also seem to manifest differently in African Americans, including with neuroinflammation markers, cognitive decline, and biomarkers. Although there are genetic risk factors for Alzheimer’s, these account for few cases in all racial groups.

References

  1. ↑ "EHS News Archives - Full Post - Episcopal High School Houston/Bellaire". www.ehshouston.org. Retrieved 2020-03-01.
  2. 1 2 3 "American Federation for Aging Research : Inside AFAR". www.afar.org. Retrieved 2020-03-01.
  3. ↑ "Dena Dubal, MD, PhD | College of Medicine". med.uky.edu. Retrieved 2020-03-01.
  4. 1 2 Dubal, Dena B. (2019-07-01). "Pathways to brain resilience". Nature Medicine. 25 (7): 1027. doi: 10.1038/s41591-019-0502-7 . ISSN   1546-170X. PMID   31270494.
  5. ↑ Chisnell, Peter; UCSF (2018-02-08). "Could a protein called klotho block dementia and aging?". University of California. Retrieved 2020-03-01.
  6. ↑ "Scientists aim to wipe out dementia and other diseases of aging". SFChronicle.com. 2017-12-08. Retrieved 2020-03-01.
  7. 1 2 3 4 Zimmer, Carl (2019-04-02). "One Day There May Be a Drug to Turbocharge the Brain. Who Should Get It?". The New York Times. ISSN   0362-4331 . Retrieved 2020-03-01.
  8. ↑ Extending the Thread of Life with Dena Dubal , retrieved 2020-03-01
  9. ↑ Dubal, Dena B.; Zhu, Lei; Sanchez, Pascal E.; Worden, Kurtresha; Broestl, Lauren; Johnson, Erik; Ho, Kaitlyn; Yu, Gui-Qiu; Kim, Daniel; Betourne, Alexander; Kuro-o, Makoto (2015-02-11). "Life Extension Factor Klotho Prevents Mortality and Enhances Cognition in hAPP Transgenic Mice". Journal of Neuroscience. 35 (6): 2358–2371. doi:10.1523/JNEUROSCI.5791-12.2015. ISSN   0270-6474. PMC   4323521 . PMID   25673831.
  10. ↑ "Can a hormone called klotho enhance cognition and hold off dementia? Yes, in mice, at least". Los Angeles Times. 2017-08-09. Retrieved 2020-03-01.
  11. ↑ "UCSF study: Hormone improves memory, motor skills in mice". East Bay Times. 2017-08-08. Retrieved 2020-03-01.
  12. ↑ Dubal, D. B.; Zhu, L.; Sanchez, P. E.; Worden, K.; Broestl, L.; Johnson, E.; Ho, K.; Yu, G.-Q.; Kim, D.; Betourne, A.; Kuro-o, M. (2015-02-11). "Life Extension Factor Klotho Prevents Mortality and Enhances Cognition in hAPP Transgenic Mice". Journal of Neuroscience. 35 (6): 2358–2371. doi:10.1523/jneurosci.5791-12.2015. ISSN   0270-6474. PMC   4323521 . PMID   25673831.
  13. ↑ Leon, Julio (2017-08-01). Peripheral Elevation of a Klotho Fragment Enhances Brain Function and Resilience in Young, Aging, and α-Synuclein Transgenic Mice. eScholarship, University of California. OCLC   1122541777.
  14. ↑ "Hormone Shows Promise as Cognition Enhancer". Hormone Shows Promise as Cognition Enhancer | UC San Francisco. Retrieved 2020-03-01.
  15. 1 2 Erickson, Claire M.; Schultz, Stephanie A.; Oh, Jennifer M.; Darst, Burcu F.; Ma, Yue; Norton, Derek; Betthauser, Tobey; Gallagher, Catherine L.; Carlsson, Cynthia M.; Bendlin, Barbara B.; Asthana, Sanjay (2019-04-16). "KLOTHO heterozygosity attenuates APOE4-related amyloid burden in preclinical AD". Neurology. 92 (16): e1878–e1889. doi:10.1212/WNL.0000000000007323. ISSN   0028-3878. PMC   6550504 . PMID   30867273.
  16. ↑ Davis, Emily J.; Lobach, Iryna; Dubal, Dena B. (2018-12-17). "Female XX sex chromosomes increase survival and extend lifespan in aging mice". Aging Cell. 18 (1): e12871. doi:10.1111/acel.12871. ISSN   1474-9718. PMC   6351820 . PMID   30560587.
  17. ↑ "What is the secret to women's longevity?". www.medicalnewstoday.com. Retrieved 2020-03-01.
  18. ↑ "Reproductive cycle may foreshadow Alzheimer's disease". EurekAlert!. Retrieved 2020-03-01.
  19. ↑ "American Federation for Aging Research : News". www.afar.org. Retrieved 2020-03-01.
  20. ↑ "The Grass Foundation - ANA Award in Neuroscience | American Neurological Association (ANA)". myana.org. Retrieved 2020-03-01.
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