David M. Holtzman | |
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Born | July 31, 1961 St. Louis, Missouri, U.S. |
Alma mater | Northwestern University University of California, San Francisco |
Known for | Mechanisms underlying neurodegeneration, including role of apoE, amyloid beta, tau, and TREM2 in pathogenesis of Alzheimer’s disease |
Awards | Paul 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 | |
Fields | Neuroscience |
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.
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]
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]
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]
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]
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]
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]
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.
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.
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 is Alzheimer's disease, Pick disease, Progressive supranuclear palsy, and corticobasal degeneration.
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.
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.
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.
Low density lipoprotein receptor-related protein 1 (LRP1), also known as alpha-2-macroglobulin receptor (A2MR), apolipoprotein E receptor (APOER) or cluster of differentiation 91 (CD91), is a protein forming a receptor found in the plasma membrane of cells involved in receptor-mediated endocytosis. In humans, the LRP1 protein is encoded by the LRP1 gene. LRP1 is also a key signalling protein and, thus, involved in various biological processes, such as lipoprotein metabolism and cell motility, and diseases, such as neurodegenerative diseases, atherosclerosis, and cancer.
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.
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).
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.
Amyloid-related imaging abnormalities (ARIA) are abnormal differences seen in magnetic resonance imaging of the brain in patients with Alzheimer's disease. ARIA is associated with anti-amyloid drugs, particularly human monoclonal antibodies such as aducanumab. There are two types of ARIA: ARIA-E and ARIA-H. The phenomenon was first seen in trials of bapineuzumab.
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.
Donanemab is a biological drug in Phase III clinical trials to determine whether it slows the progression of early Alzheimer's disease. Donanemab has shown positive results in its first trials. Donanemab was developed by the Eli Lilly and Co. and is under clinical development as a possible treatment for Alzheimer's disease. There is currently no approved cure or disease-modifying treatment for Alzheimer's disease except for lecanemab.
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.
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.
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, was bapineuzumab, but it did not show effectiveness in later-stage trials. The first drug to be FDA approved was aducanumab in 2021.
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.
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