Michael P. Murphy, Ph.D.
Position
Associate Professor
Address
Address
Room 211, Sanders-Brown Center On Aging 800 South Limestone Street Lexington, KY 40536-0230
Departmental Affiliation(s)
Molecular and Cellular Biochemistry
Research Focus
Pathogenic mechanisms and treatment of age-related amyloid diseases
Departmental Affiliations
Molecular and Cellular Biochemistry
Research Focus
Pathogenic mechanisms and treatment of age-related amyloid diseases
My lab is interested in how normal aging, genetics and environment conspire to cause Alzheimer’s disease (AD). The amyloid-β (Aβ) peptide, which deposits in the brain, is believed to cause AD. Our research is based around a working model where we hypothesize that, in most people, AD is caused by a loss of the normal regulation of the two enzymes involved in generating Aβ, β- and γ-secretase (top panel). These enzymes cut Aβ out of a larger membrane protein. In normal individuals, a small amount of Aβ is made as a byproduct of normal cellular metabolism. Cells secrete the peptide, and it is then degraded. In AD, a variety of things cause β- and γ-secretase to become more active. This leads to the generation of more Aβ, which overwhelms the brain’s clearance capacity. This eventually leads to disease. We use a variety of methods in cellular and molecular biology to understand why this happens, in the hope that this will one day lead to effective treatments.
My program is organized around understanding the contributions of three major, connected components thought to be involved in AD pathogenesis (bottom panel): (1) β-secretase, (2) the Aβ peptide itself, and (3) γ-secretase. These projects integrate synergistically, and are all extramurally funded through both federal and non-federal sources. We have a strong focus on models of disease, mainly genetically modified mice, but also in higher mammals and in cell culture based model systems.
1. β-Secretase and its Regulation in Aging and Disease. The current focus of this project is to evaluate the role of the cellular nucleic acid binding protein (CNBP) as a potential regulator of BACE1 and BACE2 activity, to determine the specificity and mechanism of this regulation, and to determine if the direct manipulation of CNBP can affect the development of disease in a mouse model of amyloidosis. These enzymes are critical for the development of Alzheimer’s disease, and may be important for other human disease processes as well. I am also interested in the role of microRNAs in the regulation of β-secretase, a collaborative project with Dr. Pete Nelson in the department of Pathology, and also a member of the Sanders-Brown Center on Aging. This component of my program is currently funded by NINDS (R01 NS058382, R01 NS061933).
2. The β-Amyloid Peptide. Chronic difficulties in assessing the role of the Aβ peptide in human disease largely stem from inadequacies in peptide preparation and inconsistencies in measurement. The purpose of this project is to develop and implement overlapping biochemical assays for the measurement of various forms of Aβ across multiple projects. This includes correlating different forms of Aβ in the human brain with both clinical and pathologic data, as well as studying the development of Aβ related pathology in animal models of AD. This component of my program is currently funded by NIA (P01 AG005119), and is part of a larger program headed by Dr. Linda Van Eldik, Director of the Sanders-Brown Center on Aging.
3. γ-Secretase and its Regulation in Aging and Disease. The current focus of this research element is on the relationship between metabolic factors involved in diabetes, and their role in regulating γ-secretase. Specifically, we are evaluating the role of the leptin receptor and systemic diabetes on the development of Aβ and tau pathology in the brain. We are creating new mouse models that recapitulate aspects of Aβ pathology (APPxPS1 knock-in mice), Aβ and tau pathology (3xTgAD mice), and diabetes (db/db mice) with viral gene transfer. This is a new aspect of my program that we began this past summer, and is currently funded by the Coins for Alzheimer’s Research Trust (CART) and the Alzheimer’s Association (IIRG-10-172905).
In the lab
Tina L Beckett (Research Analyst, Pr.)
Robin L Webb (Graduate Student)
Chris J Holler (Graduate Student)
Dana Niedowicz (Post-Doctoral Scholar)
Lab Mission
The amyloid precursor protein (APP) is potentially involved in a variety of cellular processes, but is best known for its role as the source of a small peptide fragment known as the amyloid ß peptide (Aß). This peptide plays a major role in the development of Alzheimer’s disease in the brain. Aß and APP are also likely involved in the pathology of another age-related human degenerative disease – inclusion body myositis – in muscle. Our lab studies the processes that generate Aß from APP, and the factors that regulate these at the cellular and molecular level. Our aim is to use the knowledge gained from these studies to refine model systems in which to develop novel therapeutic approaches that may one day lead to effective clinical treatments for both disorders. Recent studies include the use of widely available nonsteroidal anti-inflammatories (NSAIDs, such as ibuprofen), passive immunotherapy, and lowering of cholesterol using commonly prescribed drugs.
Recent Publications
Webb RL, Findlay KA, Green MA, Beckett TL, Murphy MP (2010). Efficient Activation of Reconstructed Rat Embryos by Cyclin-Dependent Kinase Inhibitors. PLoS One, 5(3): 1-8 (e9799).
Niedowicz DM, Beckett TL, Holler CJ, Weidner AM, Murphy MP (2010). APPΔNL695 Expression in Murine Tissue Downregulates CNBP Expression. Neurosci Lett, 482: 57-61.
Pop V, Head E, Glabe C, Studzinski CM, Weidner AM, Murphy MP, Cotman CW (2010). Ab aggregation profiles and shifts in APP processing favor amyloidogenesis in canines. Neurobiol Aging, in press.
Ebenezer PJ, Weidner AM, LeVine H, Markesbery WR, Murphy MP, Zhang L, Dasuri K, Fernandez-Kim OS, Bruce-Keller AJ, Keller JN (2010). Neuron specific toxicity of oligomeric β-amyloid: implications for JUN-kinase and oxidative stress. J Neurochem, in press.
Murphy MP, Morales J, Beckett TL, Astarita G, Piomelli D, Weidner A, Studzinski CM, Dowling ALS, Wang X, LeVine H, Kryscio RJ, Lin Y, Barrett E, Head E (2010). Changes in Cognition and Aβ Processing with Long Term Cholesterol Reduction using Atorvastatin in Aged Dogs. J Alz Dis, 22: 135-150.
Niedowicz DM, Nelson PT, Murphy MP (2010). Alzheimer’s Disease: Pathological Mechanisms and Recent Insights. Curr Neuropharmacol, in press.
Liu Y, Studzinski CM, Beckett TL, Murphy MP, Klein R, Hersh LB (2010). Circulating Neprilysin Clears Brain Amyloid. Mol Cell Neurosci, 45: 101-107.
Beckett TL, Niedowicz DM, Studzinski CM, Weidner AM, Webb RL, Holler CJ, Ahmed RR, Levine H, Murphy MP (2010). Effects of Nonsteroidal Anti-Inflammatory Drugs on Amyloid-β Pathology in Mouse Skeletal Muscle. Neurobiol Dis, 39: 449-456.
Pop V, Head E, Hill M, Gillen D, Berchtold NC, Muggenburg BA, Milgram NW, Murphy MP, Cotman CW (2010). Synergistic effects of long-term antioxidant diet and behavioral enrichment on β-amyloid load and non-amyloidogenic processing in aged canines. J Neurosci, 30(29): 9831-9839.
Ahmed RR, Holler CJ, Webb RL, Li F, Beckett TL, Murphy MP (2010). BACE1 and BACE2 enzymatic activities in Alzheimer’s Disease. J Neurochem, 112: 1045-1053.
Head E, Pop V, Sarsoza F, Kahed R, Beckett TL, Studzinski CM, Tomic JL, Glabe CG, Murphy MP (2010). Amyloid b-peptide and olgomers in the brain and CSF of aged canines. J Alzheimer Dis, 20: 637-646.
Aluise CD, Robinson RS, Beckett TL, Murphy MP, Cai J, Pierce WD, Markesbery WR, Butterfield DA (2010). Preclinical Alzheimer Disease: Brain Oxidative Stress, Aβ Peptide & Proteomics. Neurobiol Dis, 39: 221- 228.
Murphy MP, LeVine H (2010). Alzheimer’s Disease and the β-Amyloid Peptide. J Alz Dis, 19: 311-323.
Bader Lange ML, St. Clair D, Markesbery WR, Studzinski CM, Murphy MP, Butterfield DA (2010). Age-related loss of phosphlipid asymmetry in APPNLh/APPNLh x PS1P264L/PS1P264L human double mutant mice: relevance to Alzheimer disease. Neurobiol Dis, 38: 104-115.
Rosario ER, Chang L, Beckett TL, Carroll JC, Murphy MP, Stanczyk FZ, Pike CJ (2009). Age changes in serum and brain levels of androgens in male brown Norway rats. Neuroreport, 20: 1534-1537.
Liu Y, Studzinski C, Beckett T, Guan H, Hersh MA, Murphy MP, Klein R, Hersh LB (2009). Expression of Neprilysin in skeletal muscle reduces amyloid burden in a transgenic mouse model of Alzheimer disease. Mol Ther, 17(8): 1381-6.
Abdul HM, Sama MA, Furman JL, Mathis DM, Beckett TL, Weidner AM, Patel ES, Baig I, Murphy MP, LeVine H, Kraner SD, Norris CM (2009). Cognitive decline in Alzheimer’s disease is associated with selective changes in calcineurin/NFAT signaling. J Neurosci, 29(41):12957–12969.
Studzinski CM, Li F, Bruce-Keller AJ, Fernandez-Kim OS, Zhang L, Weidner AM, Markesbery WR, Murphy MP*, Keller JN (2009). Effects of short term western diet on cerebral oxidative stress and diabetes related factors in APP x PS1 knock in mice. J Neurochem, 108: 860-866. *Co-corresponding author.
Guan H, Liu Y, Daily A, Police S, Kim M-H, Oddo S, LaFerla FM, Pauly JR, Murphy MP, Hersh LB (2009). Peripherally expressed neprilysin reduces brain amyloid burden: a novel approach for treating Alzheimer’s Disease. J Neurosci Res, 87: 1462- 1473.
Jaeger LB, Dohgu S, Hwang MC, Farr SA, Murphy MP, Fleegal-Demotta MA, Lynch JL, Robinson SM, Niehoff ML, Johnson SN, Kumar VB, Banks WA (2009). Testing the Neurovascular Hypothesis of Alzheimer's Disease: LRP-1 Antisense Reduces Blood-brain Barrier Clearance and Increases Brain Levels of Amyloid-β Protein and Impairs Cognition. J Alzheimer Dis, 17: 553-570.