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| First Name: | Robert | | Last Name: | Moir | | Title: | Assistant Professor | | Advanced Degrees: | PhD | | Affiliation: | Massachusetts General Hospital & Harvard Medical School | | Department: | Neurology | | Street Address 1: | 114 16th Street | | City: | Charlestown | | State/Province: | MA | | Zip/Postal Code: | 02129-4404 | Country/Territory: | U.S.A. | | Email Address: |  |
Disclosure:
(view policy)
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Member reports no financial or other potential conflicts of interest. [Last Modified: 16 April 2009]
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View all comments by Robert Moir
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Alzheimer Disease, Prion Diseases
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A-beta PP/A-beta, Oxidative Stress, Protein structure/chemistry, Diagnosis, Neuroimmunology
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I am a full-time academic researcher. My research has, and continues to, focus on the biochemical and cellular mechanisms involved in neurodegeneration in Alzheimer's disease (AD) and aging. More specifically, receptor/ligand interactions and conditions that promote pathological protein behavior. Particular emphasis has been placed on the β-amyloid peptide (Aβ), amyloid precursor protein (APP), apolipoprotein E, low density lipoprotein receptor protein (LRP), alpha-2-macroblobulin and the presenilins (PS1 and PS2). Highlights of my research include studies that identify LRP as the cell surface receptor for APP and the receptor that mediates the first step in the pathway that ultimately leads to β-amyloid deposition in AD brain, characterization of the role and importance of metals in the pathological physiochemistry of Aβ (the principal component of amyloid in AD) and of the clinical potential of chelators in AD treatment. My experiment were the first to show the efficacy of clioquinol in dissolving Aβ aggregates and the characterization of Aβ’s role in the formation of supranuclear cataracts in the lens of AD patients. LRP-mediated Aβ clearance pathways are increasingly recognized as major targets for therapeutic intervention while the use of clioquinol as a treatment for AD is being actively pursued. Supranuclear cataracts caused by Aβ aggregation are currently being assessed as a potential diagnostic for the disease.
My more recent research focus has been on the role of redox modified forms of Aβ in AD pathology. My laboratory has characterized a sub-population of cross-linked forms of low molecular weight oligomeric Aβ that we have dubbed CAPS. These species of Aβ are highly neurotoxic and evidence is emerging that some of these species play a major, if not central, role in AD pathology. We recently published a study showing that AD patients appear to be deficient in anti-CAPS autoantibodies compared to non-demented subjects. Furthermore, levels of anti-CAPS autoantibodies correlate with age-at-onset of AD. This finding has clear and important implication for the vaccination therapies currently being developed for AD. My most recent studies have identified the normal biological function of Aβ- that of an antimicrobial peptide of the innate immune system. This finding has implications for other amyloid-forming disease proteins, including amylin from type I diabetes and PrP of prion diseases. A manuscript describing this work is currently under review at the journal Science. An RO1 grant on the role of Aβ in the actions of the innate immune system is also being prepared.
In the near future I hope to focus on our most recent finding that several disease associated amyloid forming proteins are, in fact, antimicrobial peptides with important roles in combating infection. immunity. Funding permitting, I plan to expand both my laboratory and my mentoring role.
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Moir RD, Martins RN, Small DH, Bush AI, Milward EA, Multhaup G, Beyreuther K and Masters CL. Human brain βA4 amyloid protein precursor (APP) of Alzheimer's Disease: purification and partial characterization. J. Neurochemistry 1992; 59: 1490-1498.
Bush AI, Moir RD, Rosenkranz KM and Tanzi RE. Zinc and Alzhiemer’s Disease. Science 1995; 268: 1921-1922.
Kounnas MZ, Moir RD, Rebeck CW, Bush AI, Argraves WS, Tanzi RE, Hyman BT and Strickland DK. LDL receptor-related protein, a mulitfunctional apolipoprotein E receptor, binds secreted ß-amyloid precursor protein and mediates its degradation. Cell 1995; 82: 331 40.
Moir RD, Lynch T, Bush AI, Multhaup G, Whyte S, Tanzi RE, Small DH, Beyreuther, K and Masters, CL. Relative increase in Alzheimer's disease of soluble forms of cerebral Aß amyloid protein precursor containing the Kunitz Protease Inhibitory domain. J. Biol. Chem. 1998; 273: 5013-5019.
Moir RD, Bush AI, Romano DM, Atwood CS, Huang X, Smith J and Tanzi RE. Differential effects of apolipoprotein E isoforms on metal-induced aggregation of Aß under physiological conditions. Biochemistry 1999; 38: 4595-4603.
Moir RD, Atwood CS, Tanzi RE, Huang X and Bush AI. Mounting evidence for the involvement of zinc and copper in Alzheimer's disease Eur. J. Clin. Inv. 1999; 26: 569-571.
Moir RD, Tseitlin KA, Soscia S, Hyman BT, Irizarry MC, Tanzi RE. Autoantibodies to redox-modified oligomeric Aβ are attenuated in the plasma of AD patients. J. Biol. Chem. 2005; 280: 17458-17463.
Moir RD, Tanzi RE. LRP-mediated clearance of Aß is inhibited by KPI-containing isoforms of APP. Curr. Alzheimer Res. 2005; 2: 269-273.
Tanzi, RE, Moir RD, Wagner, SL. Clearance of Alzheimer’s Aβ Peptide: The Many Roads to Perdition. Neuron 2004; 43: 605-608.
Xie Z, Dong Y, Maeda U, Moir RD, Inouye S, Culley DJ, Crosby G, Tanzi RE. Aß fibrillar aggregation inhibitor Congo Red inhibits the apoptosis induced by inhalation anesthetic isoflurane. J. Gerontol. 2008; 1247-54.
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Factors that initiate the pathological cascades that lead to neurodegeneration. |
Brogden KA, Guthmiller JM, Salzet M, Zasloff M. The nervous system and innate immunity: the neuropeptide connection. Nat Immunol. 2005 Jun;6(6):558-64.
Epstein EA, Chapman MR. Polymerizing the fibre between bacteria and host cells: the biogenesis of functional amyloid fibres. Cell Microbiol. 2008 Jul;10(7):1413-20.
Achim CL, Adame A, Dumaop W, Everall IP, Masliah E; HNRC. Increased Accumulation of Intraneuronal Amyloid beta in HIV-Infected Patients. J Neuroimmune Pharmacol. 2009 Mar 17. [Epub ahead of print]
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The Abeta is an antimicrobial peptide and AD is a disease of the innate immune system. Furthermore, Abeta associated amyloid deposits are functional structures. |
Abeta associated resistance to infection |
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