David M. Holtzman

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David M. Holtzman
David holtzman headshot.jpg
BornJuly 31, 1961
St. Louis, Missouri, U.S.
Alma mater Northwestern University
University of California, San Francisco
Known forMechanisms underlying neurodegeneration, including role of apoE, amyloid beta, tau, and TREM2 in pathogenesis of Alzheimer’s disease
AwardsPaul Beeson Physician Faculty Scholar Award, Potamkin Award for Alzheimer’s Disease Research, MetLife Award for Alzheimer’s Disease, Elected Fellow of AAAS, Member, National Academy of Medicine
Scientific career
FieldsNeuroscience
Institutions Washington University School of Medicine

David M. Holtzman is an American physician-scientist known for his work exploring the biological mechanisms underlying neurodegeneration, with a focus on Alzheimer's disease. Holtzman is former Chair of the Department of Neurology, Scientific Director of the Hope Center for Neurological Disorders, and associate director of the Knight Alzheimer's Disease Research Center at Washington University School of Medicine in St. Louis, Missouri. Holtzman's lab is known for examining how apoE4 contributes to Alzheimer's disease as well as how sleep modulates amyloid beta in the brain. His work has also examined the contributions of microglia to AD pathology.

Contents

Early life and education

Holtzman was born in St. Louis, Missouri. [1] Holtzman pursued a six-year combined Bachelor's and Medical Degree at Northwestern University in Evanston, Illinois. He obtained his Bachelors of Science in Medical Education in 1983 and his Medical Degree in 1985. [1]

After completing his MD, Holtzman pursued a residency in Neurology at the University of California, San Francisco (UCSF) from 1985 to 1989. [2] Following his residency, he completed his postdoctoral research under the mentorship of William C. Mobley at UCSF from 1989 to 1994. [2] His postdoctoral research focused on developing mouse models of neonatal stroke and neurodegeneration as well as elucidating the role neurotrophins play in modulating neuronal activity. [3] [4]

Career and research

In 1994, Holtzman became an assistant professor at Washington University in St. Louis. By 2002, Holtzman was promoted to Associate Professor of Neurology, and by 2003, he was promoted to Full Professor in the Departments of Neurology and Developmental Biology at Washington University. [5] In 2003, he also became the Chairman of the Department of Neurology, and in 2015 he became the Scientific Director of the Hope Center for Neurological Disorders. [5]

Holtzman is currently Professor of Neurology, scientific director of the Hope Center for Neurological Disorders, and director of the Knight Alzheimer's Disease Research Center at Washington University School of Medicine. He stepped down from his position as department chairman in 2021. [6]   The Holtzman Lab is dedicated to exploring the biological mechanisms underlying neurodegeneration. [7] Holtzman's work has studied mechanisms by which apoE, amyloid beta, and tau metabolism are implicated in neurodegeneration in the context of Alzheimer's disease. [7] Holtzman is also a co-founder of C2N Diagnostics, LLC. Holtzman and his former trainee, Randall Bateman, developed C2N Diagnostics in 2007 with the goal of increasing the understanding the molecular mechanisms underlying neurological diseases through measurements of concentration and metabolism of CNS-derived biomolecules. [8] [9]

Apolipoprotein E and Alzheimer's disease

Holtzman and his lab have examined the role of apoE in AD pathogenesis. [10] Both the ε4 and ε2 APOE alleles increase the risk of developing AD, with an approximately 12-fold AD risk for those with two copies of ε4 allele. [7] Holtzman's Lab has shown that apoE contributes to AD susceptibility and pathogenesis by its modulation of Aβ clearance and aggregation. Specifically, they have found that different isoforms of apoE have differential effects on soluble Aβ clearance. [11]

Immunotherapeutic approaches for Alzheimer's disease

In 2001, Holtzman and his team published a paper showing that administration of the anti-Aβ antibody (m266) in mice changes the equilibrium of Aβ across the CNS and blood plasma leading to increased Aβ sequestration in plasma which reduces the burden of Aβ in the brain. [12] This antibody, m266, was licensed to Eli Lilly and humanized.  Using the humanized anti-Aβ antibody, Solanezumab, Eli Lilly began a series of clinical trials to discern the therapeutic potential of anti-Aβ immunotherapy in humans with AD. Results of these trials were disappointing. Solanezunmab treatment did not meet the primary endpoint of the clinical trials in mild AD, however, a clinical trial known as A4 in “presymptomatic” AD is still ongoing. [13] Holtzman's lab has also focused on anti-tau immunotherapeutic approaches to treating AD, and this approach is now in phase II clinical trials following licensing of an anti-tau antibody his lab developed with AbbVie. [14]

Amyloid and Synaptic Activity

Along with other groups, Holtzman and his team were able to discern that synaptic activity influences Aβ levels in the brain. [15] They also found that Aβ deposition is brain region dependent, specifically correlating with regions involved in the default mode network. These findings suggest that increased metabolic demands and activity levels lead to higher soluble Aβ loads in these brain regions involved in the default mode network. [16]

Sleep and Alzheimer’s Disease

The Holtzman lab has made important advances in our understanding of how sleep cycles influence Aβ concentrations in the brain interstitial fluid and Cerebrospinal Fluid. They found that Aβ and tau are higher during wakefulness and lower during sleep, and that these differences in Aβ and tau dynamics are driven by synaptic activity differences and orexin signaling. [17] [18] Following this work, Holtzman and his team found that once Aβ has been deposited, it results in sleep disruptions and further Aβ aggregation in a positive feedback loop promoting increased pathology. [17] They also found that sleep cycles are implicated in the release of extracellular tau and that less NREM sleep is linked to increased tau pathology. [19]

Awards and honors

Select publications

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. Both neurons and oligodendrocytes produce and release Aβ in the brain, contributing to formation of amyloid plaques. 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. 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. Plaques form when Aβ misfolds and aggregates into oligomers and longer polymers, the latter of which are characteristic of amyloid.

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

Tauopathies are a class of neurodegenerative diseases characterized by the aggregation of abnormal tau protein. Hyperphosphorylation of tau proteins causes them to dissociate from microtubules and form insoluble aggregates called neurofibrillary tangles. Various neuropathologic phenotypes have been described based on the anatomical regions and cell types involved as well as the unique tau isoforms making up these deposits. The designation 'primary tauopathy' is assigned to disorders where the predominant feature is the deposition of tau protein. Alternatively, diseases exhibiting tau pathologies attributed to different and varied underlying causes are termed 'secondary tauopathies'. Some neuropathologic phenotypes involving tau protein are Alzheimer's disease, frontotemporal dementia, progressive supranuclear palsy, and corticobasal degeneration.

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

A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their 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">Low-density lipoprotein receptor-related protein 8</span> Cell surface receptor, part of the low-density lipoprotein receptor family

Low-density lipoprotein receptor-related protein 8 (LRP8), also known as apolipoprotein E receptor 2 (ApoER2), is a protein that in humans is encoded by the LRP8 gene. ApoER2 is a cell surface receptor that is part of the low-density lipoprotein receptor family. These receptors function in signal transduction and endocytosis of specific ligands. Through interactions with one of its ligands, reelin, ApoER2 plays an important role in embryonic neuronal migration and postnatal long-term potentiation. Another LDL family receptor, VLDLR, also interacts with reelin, and together these two receptors influence brain development and function. Decreased expression of ApoER2 is associated with certain neurological diseases.

<span class="mw-page-title-main">Proteinopathy</span> Diseases caused by abnormal protein structure

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.

<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 average life expectancy following diagnosis is three to twelve years.

Solanezumab is a monoclonal antibody being investigated by Eli Lilly as a neuroprotector for patients with Alzheimer's disease. The drug originally attracted extensive media coverage proclaiming it a breakthrough, but it has failed to show promise in Phase III trials.

<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 Director of the Centre for Discovery Brain Sciences at the University of Edinburgh.

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.

Alison Mary Goate is the Jean C. and James W. Crystal Professor and Chair of the Department of Genetics and Genomic Sciences and Director of the Loeb Center for Alzheimer's Disease at Icahn School of Medicine at Mount Sinai, New York City. She was previously professor of genetics in psychiatry, professor of genetics, and professor of neurology at Washington University School of Medicine.

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.

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.

<span class="mw-page-title-main">Yo-El Ju</span> Neuroscience professor

Yo-El Ju is the Barbara Burton and Reuben Morriss III Professor of Neurology at the Washington University School of Medicine. She co-directs the Center on Biological Rhythms and Sleep (COBRAS) and is a member of the Hope Center for Neurological Diseases at Washington University. Clinically, she sees patients at Barnes-Jewish Hospital for parasomnia, narcolepsy, restless legs syndrome, and obstructive sleep apnea. Ju's team has made multiple significant contributions to the field of sleep medicine and neurology in unveiling the complex relationship between sleep, amyloid deposition and neurodegenerative diseases such as Alzheimer's, opening new possibilities for clinical treatment. As of April 2023, the most cited work from her lab is their 2017 paper in Brain: A Journal of Neurology that showed cerebrospinal fluid (CSF) amyloid-beta protein level increases due to slow-wave sleep disruption.

Anti-amyloid drugs, also known as anti-amyloid antibodies (AAA), are a class of monoclonal antibodies developed to treat Alzheimer's disease. The first drug in the class to be developed, in the early 2000s, is bapineuzumab, but it did not show effectiveness in later-stage trials. The first drug to be approved by the US Food and Drug Administration (FDA) is aducanumab—in 2021.

<span class="mw-page-title-main">Alzheimer's disease and COVID-19</span>

Studies have shown that Alzheimer's disease (AD) patients are at an increased risk of morbidity and mortality from SARS-CoV-2, the virus that causes COVID-19. AD is the most common cause of dementia worldwide and is clinically defined by amyloid beta plaques, neurofibrillary tangles, and activation of the brain's immune system. While COVID-19 has been known to more severely impact elderly populations, AD patients have been shown to have a higher rate of SARS-CoV-2 infection compared to cognitively normal patients. The disproportionate risk of COVID-19 in AD patients is thought to arise from an interplay of biological and social factors between the two diseases. Many common biological pathways are shared between COVID-19 and AD, notably those involved in inflammation. Genetic factors that put individuals at risk for AD, such as the APOE4 genotype, are associated with worse outcomes during SARS-CoV-2 infection. Cognitive impairment in AD may prevent patients from following proper public health guidelines, such as masking and social distancing, increasing their risk of infection. Additionally, studies have shown cognitively normal COVID-19 patients are at an increased risk of AD diagnosis following recovery, suggesting that COVID-19 has the potential to cause AD.

David Lozoff Brody is an American neurologist, academic, and author most known for his research on the clinical treatment of traumatic brain injury (TBI) and neurodegenerative diseases in civilian and military personnel. He is a Clinical Neurologist at the Walter Reed National Military Medical Center and a professor of Neurology at Uniformed Services University of the Health Sciences, as well as a professor of Neurology and Biomedical Engineering at Washington University.

References

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  2. 1 2 3 "195: Dr. David Holtzman: Untangling the Mechanisms and Mysteries of Alzheimer's Disease". People Behind the Science Podcast. 2014-12-19. Retrieved 2020-12-30.
  3. ↑ Holtzman, D. M.; Li, Y. W.; DeArmond, S. J.; McKinley, M. P.; Gage, F. H.; Epstein, C. J.; Mobley, W. C. (1992-02-15). "Mouse model of neurodegeneration: atrophy of basal forebrain cholinergic neurons in trisomy 16 transplants". Proceedings of the National Academy of Sciences of the United States of America. 89 (4): 1383–1387. Bibcode:1992PNAS...89.1383H. doi: 10.1073/pnas.89.4.1383 . ISSN   0027-8424. PMC   48455 . PMID   1741393.
  4. ↑ Holtzman, D. M.; Li, Y.; Parada, L. F.; Kinsman, S.; Chen, C. K.; Valletta, J. S.; Zhou, J.; Long, J. B.; Mobley, W. C. (September 1992). "p140trk mRNA marks NGF-responsive forebrain neurons: evidence that trk gene expression is induced by NGF". Neuron. 9 (3): 465–478. doi:10.1016/0896-6273(92)90184-f. ISSN   0896-6273. PMID   1524827. S2CID   25740693.
  5. 1 2 "Scientific Advisors". C2N Diagnostics. Archived from the original on 2021-03-02. Retrieved 2020-12-30.
  6. ↑ "Charles F. and Joanne Knight ADRC at Washington University". knightadrc.wustl.edu. Retrieved 2020-12-30.
  7. 1 2 3 "About the Lab". neuro.wustl.edu. Retrieved 2020-12-30.
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  10. ↑ "David Holtzman, MD | ANA 2019". 2019.myana.org. Archived from the original on 2021-01-17. Retrieved 2020-12-30.
  11. ↑ Kim, Jungsu; Castellano, Joseph M.; Jiang, Hong; Basak, Jacob M.; Parsadanian, Maia; Pham, Vi; Mason, Stephanie M.; Paul, Steven M.; Holtzman, David M. (2009-12-10). "Overexpression of low-density lipoprotein receptor in the brain inhibits amyloid deposition and increases extracellular A beta clearance". Neuron. 64 (5): 632–644. doi:10.1016/j.neuron.2009.11.013. ISSN   1097-4199. PMC   2787195 . PMID   20005821.
  12. ↑ DeMattos, Ronald B.; Bales, Kelly R.; Cummins, David J.; Dodart, Jean-Cosme; Paul, Steven M.; Holtzman, David M. (2001-07-17). "Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease". Proceedings of the National Academy of Sciences of the United States of America. 98 (15): 8850–8855. Bibcode:2001PNAS...98.8850D. doi: 10.1073/pnas.151261398 . ISSN   0027-8424. PMC   37524 . PMID   11438712.
  13. ↑ "Clinical Trial of Solanezumab for Older Individuals Who May be at Risk for Memory Loss - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2020-12-30.
  14. ↑ Tan, Victoria. "ABBV-8E12 - Alzheimer's News Today" . Retrieved 2020-12-30.
  15. ↑ Cirrito, John R.; Yamada, Kelvin A.; Finn, Mary Beth; Sloviter, Robert S.; Bales, Kelly R.; May, Patrick C.; Schoepp, Darryle D.; Paul, Steven M.; Mennerick, Steven; Holtzman, David M. (2005-12-22). "Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo". Neuron. 48 (6): 913–922. doi: 10.1016/j.neuron.2005.10.028 . ISSN   0896-6273. PMID   16364896. S2CID   117506.
  16. ↑ Bero, Adam W.; Yan, Ping; Roh, Jee Hoon; Cirrito, John R.; Stewart, Floy R.; Raichle, Marcus E.; Lee, Jin-Moo; Holtzman, David M. (June 2011). "Neuronal activity regulates the regional vulnerability to amyloid-β deposition". Nature Neuroscience. 14 (6): 750–756. doi:10.1038/nn.2801. ISSN   1546-1726. PMC   3102784 . PMID   21532579.
  17. 1 2 Kang, Jae-Eun; Lim, Miranda M.; Bateman, Randall J.; Lee, James J.; Smyth, Liam P.; Cirrito, John R.; Fujiki, Nobuhiro; Nishino, Seiji; Holtzman, David M. (2009-11-13). "Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle". Science. 326 (5955): 1005–1007. Bibcode:2009Sci...326.1005K. doi:10.1126/science.1180962. ISSN   1095-9203. PMC   2789838 . PMID   19779148.
  18. 1 2 Holth, Jerrah K.; Fritschi, Sarah K.; Wang, Chanung; Pedersen, Nigel P.; Cirrito, John R.; Mahan, Thomas E.; Finn, Mary Beth; Manis, Melissa; Geerling, Joel C.; Fuller, Patrick M.; Lucey, Brendan P. (February 22, 2019). "The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans". Science. 363 (6429): 880–884. Bibcode:2019Sci...363..880H. doi:10.1126/science.aav2546. ISSN   1095-9203. PMC   6410369 . PMID   30679382.
  19. ↑ "New Research Shows How Sleep Could Ward Off Alzheimer's Disease". Time. Retrieved 2020-12-30.
  20. ↑ cspcs.sanford.duke.edu/. 1994 https://cspcs.sanford.duke.edu/sites/default/files/descriptive/aging_research_program.pdf. Archived (PDF) from the original on 2011-08-09. Retrieved December 30, 2020.{{cite web}}: Missing or empty |title= (help)
  21. ↑ "Holtzman named the Hagemann Professor of neurology" (PDF). adrcpress.wustl.edu/. 2001. Retrieved December 30, 2020.
  22. 1 2 "David M. Holtzman, MD". www.cecentral.com. Retrieved 2020-12-30.
  23. ↑ "New AAAS Fellows Recognized for Their Contributions to Advancing Science | American Association for the Advancement of Science". www.aaas.org. Retrieved 2020-12-30.
  24. ↑ "Message from ANA President Dr. David Holtzman | American Neurological Association (ANA)". myana.org. Retrieved 2020-12-30.
  25. ↑ "43 Members of National Academies of Sciences, Engineering, and Medicine Elected to 2017 Class of National Academy of Inventors Fellows". www8.nationalacademies.org. Retrieved 2020-12-30.
  26. ↑ Leyns, Cheryl E. G.; Gratuze, Maud; Narasimhan, Sneha; Jain, Nimansha; Koscal, Lauren J.; Jiang, Hong; Manis, Melissa; Colonna, Marco; Lee, Virginia M. Y.; Ulrich, Jason D.; Holtzman, David M. (August 2019). "TREM2 function impedes tau seeding in neuritic plaques". Nature Neuroscience. 22 (8): 1217–1222. doi:10.1038/s41593-019-0433-0. ISSN   1546-1726. PMC   6660358 . PMID   31235932.
  27. ↑ Yanamandra, Kiran; Kfoury, Najla; Jiang, Hong; Mahan, Thomas E.; Ma, Shengmei; Maloney, Susan E.; Wozniak, David F.; Diamond, Marc I.; Holtzman, David M. (2013-10-16). "Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo". Neuron. 80 (2): 402–414. doi:10.1016/j.neuron.2013.07.046. ISSN   1097-4199. PMC   3924573 . PMID   24075978.
  28. ↑ Kang, Jae-Eun; Lim, Miranda M.; Bateman, Randall J.; Lee, James J.; Smyth, Liam P.; Cirrito, John R.; Fujiki, Nobuhiro; Nishino, Seiji; Holtzman, David M. (2009-11-13). "Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle". Science. 326 (5955): 1005–1007. Bibcode:2009Sci...326.1005K. doi:10.1126/science.1180962. ISSN   1095-9203. PMC   2789838 . PMID   19779148.
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