Miguel Pappolla,

JAD profile

Associate Editor

Term Expiration: 

12/31/2026

Affiliation(s): 

University of Texas Medical Branch and Private Practice

Lab URL: 

http://www.NEUROLOGISTCLINIC.com

Areas of Interest: 

Brain Aging. Pain Medicine

Biography & Research: 

Dr. Pappolla's contributions to Alzheimer’s disease include: 1-Publication of the first paper identifying markers of oxidative stress associated with the neuropathologic lesions of Alzheimer’s disease. Before this publication, there was only one paper proposing such a mechanism without neuropathologic information. Subsequent research in this area led to the identification of critical pathways of neuronal death in Alzheimer’s disease (AD) (oxidation and inflammation). Collaborative work with many research groups including Dr. Mark Smith and Dr. George Perry and numerous additional collaborations (i.e., Alzheimer’s Disease Cooperative Study Group; ADCS) were pursued with the purpose of developing neuroprotective agents as potential therapeutic agents for AD and other neurodegenerative conditions (see below, ongoing). The impact of this work is partially reflected in its citation index (see below) that includes citations in the most influential papers in this area of AD research. 4 representative papers are listed (see below). -Pappolla MA, Omar RA, Kim KS, Robakis NK: Immunohistochemical Evidence of Oxidative Stress in Alzheimer's Disease. Am J Pathol, 140:621-628, 1992. Citations: OVER 500. -Pappolla MA, Chyan Y-J, Omar RA, Hsiao K, Perry G, Smith MA, Bozner P: Evidence of oxidative Stress and in Vivo Neurotoxicity of -Amyloid in a Transgenic Mouse Model of Alzheimer’s Disease. Am J Pathol, 152:871-877, 1998. Citations: Over 400. -Nunomura A, Perry G, Pappolla MA, Wade R, Hirai K, Chiba S, Smith MA: RNA Oxidation is a Prominent Feature of Vulnerable Neurons in Alzheimer Disease. J Neuroscience, 15:1959-1964, 1999. Citations: 632. -Smith MA, Hirai K, Hsiao K, Pappolla MA, Harris LR, Perry G: Amyloid- Deposition in Alzheimer Transgenic Mice is Associated with Oxidative Stress. J Neurochem, 70:2212-2215, 1998. Citations: Over 700. 2- In collaboration with Dr. Larry Refolo, Dr Suzana Petanceska at the NIH and others, Dr. Pappolla conducted groundbreaking research on hypercholesterolemia. This is now an established mid-life (early) risk factor for Alzheimer's disease. Our findings were corroborated by several landmark human epidemiological studies which also reference our studies. Representative papers: -Refolo LM, Wang R, Tint S, Sambamurti, Malester BT, Francois JL, Duff K, Pappolla MA: Hypercholesterolemia Accelerates Amyloid Pathology in a Transgenic Mouse Model of Alzheimer’s Amyloidosis. Neurobiol Dis, 7:321-331, 2000. Citations: Over 1300 -Refolo LM, Pappolla MA , Malester BT, Francois JL, Bryant-Thomas T, Wang R, Tint GS, Sambamurti K, Duff KE: A Cholesterol Lowering Drug Reduces beta-amyloid Deposition in a Transgenic Mouse Model of Alzheimer’s Amyloidosis. Neurobiol Dis, 8:890-899, 2001. Citations: Over 700. -Pappolla MA, Bryant-Thomas TK, Herbert D, Pacheco J, Fabra Garcia M, Manjon M, Girones X, Henry TL, Matsubara E, Zambon D, Wolozin B, Petanceska SS, Sano M, Cruz-Sanchez FF, Thal LJ, Refolo LM: Hypercholesterolemia is an Early Risk Factor for the Development of Alzheimer Amyloid Pathology. Neurology. 61:199-205, 2003. Citations: Over 400 -Petanceska SS, DeRosa S, Sharma A, Diaz N, Duff K, Tint SG, Refolo LM, Pappolla M. Changes in apolipoprotein E expression in response to dietary and pharmacological modulation of cholesterol. J Mol Neurosci. 2003;20(3):395-406. This paper is important under a mechanistic standpoint because it shows that increased expression of apoE4, induced by hypercholesterolemia, leads to higher amyloid load. This is a critical link in the neuropathologic cascade leading to AD. More recenly we identified that in addition to hypercholesterolemia, alterations of the LDL receptor (LDLr) function are implicated in the development of human cognitive abnormalities. In one of our studies, we showed for the first time in humans that the LDLr plays a critical role in cognition, something that has been suspected for sometime but never showed in humans. Our data demonstrated that the carriers of an LDLr mutation developed midlife cognitive abnormalities associated with cortical (not subcortical) pathology (Zambón D, Quintana M… Pappolla MA. Higher Incidence of Mild Cognitive Impairment in Familial Hypercholesterolemia. Am J Med. 2010 Mar;123(3):267-274). 3-Our lab has been involved in the development of neuroprotective agents for neurodegenerative disorders for many years. This research identified that melatonin was a powerful neuroprotective molecule in multiple models of Alzheimer’s disease. We showed, for the first time, that melatonin was a neuroprotective agent against Abeta in multiple in vitro and transgenic models. We also show that melatonin is also an inhibitor of beta amyloid aggregation. These original findings were confirmed in multiple independent laboratories around the world and led to the development of more powerful melatonin related analogs as neuroprotective agents, not only for AD but for other neurodegenerative disorders. Research in this area is currently ongoing in several laboratories including pharmaceutical companies. Representative papers: -Pappolla MA, Sos M, Omar RA, Bick RJ, Hickson-Bick DLM, Reiter RJ, Efthimiopoulos S, Robakis NK: Melatonin Prevents Death of Neuroblastoma Cells Exposed to the Alzheimer Amyloid Peptide. J Neurosci, 17:1683-1690, 1997. Citations: Over 500. -Pappolla MA, Bozner P, Soto C, Shao H, Robakis NK, Zagorski M, Frangione B, Ghiso J: Inhibition of Alzheimer beta-Fibrillogenesis by Melatonin. J Biol Chem, 273:7185-7188, 1998. Citations: Over 400. -Pappolla MA, et al. Uses for indole-3-propionic acids and salts and esters thereof. US Patent number: 6395768 -Pappolla, et al Method for delaying the onset of Alzheimer's disease and for treatment or delaying the onset of other amyloidosis-related diseases/disorders. US Patent number: 6274615 -Pappolla et al, Use of melatonin to prevent cytotoxic effects of amyloid beta protein. US Patent number: 5958964 For more information on pharmaceutical applications of these discoveries, please visit: http://www.prnewswire.com/news-releases/viropharma-licenses-rights-from-intellect-neurosciences-for-product-candidate-for-friedreichs-ataxia-130841723.html 4-Recently, Dr. Pappolla identified a novel clearance pathway for beta-amyloid through the lymphatic system. Although this pathway has been suspected for some time by various research groups, it had never been experimentally demonstrated. The paper was well received and commented on various forums including alzforum.org and recently cited in Nature Reviews. One of the comments (by Dr. T. Wiesnewski in alzforum.org) summarizes the potential impact of the findings: “This is a most interesting paper. Inadequate clearance of Aβ from the brain is considered to play a critical role in amyloid accumulation of late-onset Alzheimer's disease (LOAD). Despite the research efforts of the last three decades, the role of the lymphatic system in amyloid clearance has been largely ignored. The brain lacks lymphatic channels; however, as Dr. Pappolla emphasizes in this study, circulation of immune-competent cells, such as dendritic and perivascular cells, between brain and peripheral lymph nodes is well established. A role for glymphatic interstitial fluid (ISF) bulk flow clearance, which drains into the peripheral lymphatics, in regulating brain Aß levels, is being recognized (Iliff JJ et al., 2013). The glymphatic system is the brain's version of the peripheral lymphatic system. Peripheral lymph nodes participate in immune surveillance and antigen presentation in the brain, particularly during neuro-inflammatory processes. Recently, a substantial number of new genes that associate with increased risk of AD has been discovered. Because the products of many of these genes are involved in immune modulatory functions, the study by Pappolla et al. highlights a new perspective in AD pathogenesis, which may have significant therapeutic impact in this disease. -Pappolla MA, Sambamurti K, Pacheco-Quinto J, Vidal R, Poeggeler B, Matsubara E. Evidence for Lymphatic A Clearance in Alzheimer’s Transgenic Mice. Neurobiol Dis. 2014 Nov; 71:215-9. 5-Briefly, additional contributions to science include: A-First report of blood brain barrier abnormalities in the aged brain. These early papers stimulated additional research, but the original reports remained largely ignored in terms of citation index (subsequent papers based on our studies received thousands of citations). Almost three decades ago, we postulated the hypothesis that blood brain barrier breakdown in aging brain contributes to some aspects of age related neurodegeneration. In a series of papers, Dr. Pappolla in collaoration with Dr. A. C. Andorn demonstrated a blood brain barrier (BBB) breakdown and leakage of serum proteins in aged (but not young) human brain (Pappolla and Andorn, 1987; Andorn et al., 1986; Andorn and Pappolla, 1989). -Pappolla MA, Andorn AC. Serum protein leakage in aged human brain and inhibition of ligand binding at alpha 2-adrenergic and cholinergic binding sites. Synapse. 1987;1(1):82-9. Andorn AC, Pappolla MA, Fox H, Klemens FK, Martello PA. Human serum Cohn fraction IV (alpha-globulin [correction of globin] enriched) inhibits ligand binding at neurotransmitter receptors in human brain. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4572-5. -Andorn AC, Pappolla MA. Serum protein interactions with neurotransmitter receptors: implications for Alzheimer's disease. Prog Clin Biol Res. 1989;317:695-701. We were the first to propose the hypothesis that glycation is a mechanism contributing to protein insolubility in Alzheimer’s disease. -Pappolla MA, et al: Ultrastructural Evidence that Insoluble Microtubules Are a Component of Neurofibrillary Tangles. Eur Arch Psychiatr Neurol Sci, 239:314-319, 1990. Dr. Pappolla's includes medical residencies and fellowships in Neurology and Pain Medicine (Anesthesia based) and also in Clinical Pathology, Anatomic Pathology, and Neuropathology. This training required 10 additional years of formal medical education (following graduation from medical school), all of which were pursued in programs accredited by the American Board of Medical Specialties. Dr. Pappolla holds board-certifications in 5 disciplines of Medicine (Pain Management, Neurology, Anatomic Pathology, Clinical Pathology and Neuropathology). Dr. Pappolla has served the public at large for over 20 years as a consultant for the NIH and a full Professor or Faculty at several of the most prestigious medical schools in the USA (LSU New Orleans, Mount Sinai Medical School in New York City, University of Texas at Houston) where he taught Neurosciences to medical students and medical residents for over 30 years. He has also served as Chairman of Neurology and Director of Neurosciences in one of the largest tertiary care centers in Mississippi, till about the time when his practice was disrupted by hurricane Katrina, when he relocated to Houston, Texas. In addition to participating in several research projects, he also practices pain medicine in Houston, Texas in a private practice setting (www.neurologistclinic.com).