The Laboratory of Dennis J. Selkoe, M.D.

Harvard Medical School
Center for Neurologic Diseases
Brigham & Women’s Hospital, Boston, MA

Selkoe Publications 2000-2007

Vekrellis K, Ye Z, Qiu WQ, Walsh D, Hartley D, Chesneau V, Rosner MR, Selkoe DJ.  Neurons regulate extracellular levels of  amyloid ß-protein  via proteolysis by insulin-degrading enzyme.  J Neurosci, 2000; 20: 1657-1665.

Kimberly WT, Xia W, Rahmati T, Wolfe S, Selkoe DJ.  The transmembrane aspartates in presenilin 1 and 2 are obligatory for g-secretase activity and amyloid ß-protein generation.  J Biol Chem 2000; 275: 3173-3178.

Stoltzner SE, Grenfell TJ, Mori C, Wisniewski KE, Wisniewski TM, Selkoe DJ, Lemere CA.  Temporal accrual of complement proteins in amyloid plaques in Down syndrome with Alzheimer’s disease.  Am J Pathol 2000; 156: 489-499.

Weiner HL, Lemere CA, Mar4on R, Spooner ET, Grenfell TJ, Mori C, Issazadeh S, Hancock WW, Selkoe DJ.  Nasal administration of amyloid ß-protein decreases cerebral amyloid burden in a mouse model of Alzheimer’s disease.  Annals Neurol, 2000; 48: 567-579..

Berezovska O, Jack C, McLean P, Aster JC, Hicks C, Xia W, Wolfe MS, Kimberly WT, Weinmaster G, Selkoe DJ, Hyman BT.  Aspartate mutations in presenilin and g-secretase inhibitors both impair Notch 1 proteolysis and nuclear translocation with relative preservation of Notch signaling.  J. Neurochem. 2000, 75; 583-593.

Xia W, Ray WJ, Ostazewski BL, Rahmati T, Kimberly WT, Wolfe MS, Zhang J, Goate AM, Selkoe DJ.  Complex formation of presenilin with APP C-terminal fragments at sites of Aß generation: Evidence for the direct involvement of presenilin in g-secretase activity.  Proc Natl Acad Sci USA, 2000; 97: 9299-9304.

Esler WP, Kimberly WT, Ostaszewski BL, Diehl TS, Moore CL, Tsai-J-Y, Rahmati T, Selkoe DJ, Wolfe MS.  Transition-state analogue inhibitors of g-secretase bind directly to presenilin-1.  Nature Cell Biology 2000, 2: 428-434.

Walsh DM, Tseng BP, Rydel RD, Podlisny MB, Selkoe DJ.  The oligomerization of amyloid ß-protein begins intracellularly in cells derived from human brain.  Biochemistry 2000; 39:10831-10839.

Fezoui Y, Hartley DM, Harper JD, Khurana R, Walsh DM, Condron MM, Selkoe DJ, Lansbury Jr PT, Fink AL, Teplow DB.  An improved method of preparing the amyloid ß-protein for fibrillogenesis and neurotoxicity experiments.  Amyloid: Int. J. Exp. Clin. Invest. 2000; 7: 166-178.

Moore CL, Leatherwood DD, Diehl TS, Selkoe DJ, Wolfe MS.  Difluoro ketone peptidoimetics suggest a large S1 pocket for Alzheimer’s g-secretase: Implications for inhibitor design.  J Med Chem, 2000, 43: 3434-3442.

Chesneau V, Vekrellis K, Rosner MR, Selkoe DJ.  Purified recombinant insulin-degrading enzyme degrades amyloid ß-protein but does not promote its oligomerization.  Biochem J 2000; 351: 509-516.

Fezoui Y, Hartley DM, Walsh DM, Selkoe DJ, Osterhout JJ, Teplow DB.  A de novo degisned helix-turn-helix peptide forms nontoxic amyloid fibrils.  Nat Struct Biol 2000; 7: 1095-1099.

Bertram L, Blacker D, Mullin K, Keeney D, Jones J, Basu S, Yhu S, McInnis MG, Go RC, Vekrellis K, Selkoe DJ, Saunders AJ, Tanzi RE.  Evidence for genetic linkage of Alzheimer’s disease to chromosome 10q.  Science 2000; 290: 2302-2303.

Walsh DM, Hartley DM, Condron MM, Selkoe DJ, Teplow DB.  In vitro studies of amyloid ß-protein fibril assembly and toxicity provide clues to the etiology of Flemish variant (Ala692 à Gly) Alzheimer’s disease.  Biochem J, 2001; 355:869-877.

Sharon R, Goldberg M, Bar-Josef I, Betensky R, Shen J, Selkoe DJ.  a-Synuclein occurs in lipid-rich high molecular weight complexes, binds fatty acids and shows homology to the fatty acid binding proteins.  Proc Nat Acad Sci USA, 2001; 98: 9110-9115.

Shimura H, Schlossmacher MG, Hattori N, Frosch MP, Trockenbacher A, Schneider R, Mizuno Y, Kosik KS, Selkoe DJ.  Ubiquitination of a new form of a-synuclein by parkin from human brain:  Implications for Parkinson’s disease.  Science, 2001; 293: 263-269.

Kimberly WT, Zheng JB, Guenette S, Selkoe DJ.  The intracellular domain of the ß-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a Notch-like manner.  J Biol Chem, 2001, 276: 40288-40292.

Mori C, Spooner ET, Wisniewski KE, Wisniewski TM, Yamaguchi H, Saido TC, Tolan DR, Selkoe DJ, Lemere CA.  Intraneuronal Aß42 Accumulation in Down Syndrome Brain.   Amyloid  2002:  9(2): pp. 88-102.

Esler WP, Das C, Campbell WA, Kimberly WT, Kornilova AY, Diehl TS, Ye W, Ostaszewski BL, Xia W, Selkoe DJ, Wolfe MS.   Amyloid-lowering isocoumarins are not diret inhibitors of g-secretase.  Nat Cell Biol 2002; 4: E110-112.

Esler W, Kimberly WT, Ostaszewski BL, Diehl T, Selkoe DJ, Wolfe MS.  Activity dependent isolation of the presenilin/g-secretase complex reveals nicastrin and a g substrate.  Proc Natl Acad Sci USA, 2002, 99: 2720-2725.

Walsh DM, Klyubin I, Fadeeva J, Cullen WK, Anwyl R, Wolfe MS, Rowan MH, Selkoe  DJ.  Naturally secreted oligomers of the Alzheimer amyloid ß-protein potently inhibit hippocampal long-term potentiation in vivo.  Nature, 2002, 416: 535-539.

Zhang J, Ye W, Wang R, Wolfe MS, Greenberg BD, Selkoe DJ.  Proteolysis of chimeric APP proteins containing the Notch transmembrane domain yields an Aß-like peptide.  J Biol Chem, 2002, 277: 15069-15075.

Schlossmacher MG, Frosch MP, Gai WP, Medina M, Sharma N, Forno L, Ochiishi T, Shimura H, Hattori N, Langston JW, Mizuno Y, Hyman BT, Selkoe DJ, Kosik KS.  Parkin Localizes to the Lewy Bodies of Parkinson’s Disease and Dementia with Lewy Bodies.  Am J. Pathol, 2002; 160: 1655-1667.

Craft DL, Wein LM, Selkoe DJ.  A mathematical model of the impact of novel treatments on the Aß burden in the Alzheimer’s brain, CSF and plasma.  Bulletin of Mathematical Biology 2002; 64: 1011-1031.

Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ.  Complex N-linked glycosylated Nicastrin associates with active g-secretase and undergoes tight cellular regulation.  J Biol Chem 2002, 277: 35113-35117 .

Esler WP, Das C, Campbell WA, Kimberly WT, Kornilova AY, Diehl TS, Ye W, Ostaszewski BL, Xia W, Selkoe DJ, Wolfe MS.  Amyloid-lowering isocoumarins are not direct inhibitors of gamma-secretase. Nat Cell Biol. 2002; 4:E110-1.

W. T. Kimberly, W. P. Esler, W. Ye, B. L. Ostaszewski, J. Gao, T. S. Diehl, D. J. Selkoe, and M. S. Wolfe.  Notch and amyloid precursor protein are cleaved by similar g-secretase(s).  Biochemistry, 2003; 42: 137-144.

Sharon R, Bar-Joseph I, Frosch MP,  Selkoe DJ.  The formation of highly soluble oligomers of a-synuclein is regulated by fatty acids and enhanced in Parkinson’s disease.  Neuron, 2003; 37: 583-595.

Farris RW, Chang Y, Mansourian S, Lindsley L, Echman EA, Frosch MP, Echman CBN, Tanzi RE, Selkoe DJ, Guenette S.  Insulin-degrading enzyme regulates the levels of insulin, amyloid ß-protein  and the APP intracellular domain in vivo.  Proc Natl Acad Sci USA, , 2003;100:4162-4167.

Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ.  g-secretase is a membrane protease complex comprised of presenilin, nicastrin, Aph-1 and Pen-2.  Proc Natl Acad Sci USA, 2003; 100: 6382-6387.

Walsh DM, Fadeeva JV, Lavoie MJ, Paliga K, Eggert S, Kimberly WT, Selkoe, DJ.  g-Secretase Cleavage and Binding to Fe65 Regulate the Nuclear Translocation of the APP Family of Proteins.  Biochemistry, 2003, 42: 6664-6673.

Ye C, Walsh DM, Vassilev PM, Selkoe DJ, Hartley DM.  Protofibrils of amyloid ß-protein  inhibit specific K+ currents in neocortical cultures.  Neurobiol. Dis., 2003; 13: 177-190.

Lemere CA, Spooner ET, LaFrancois J, Malester B, Mori C, Leverone JF, Matsuoka Y, Taylor JW, DeMattos RB, Holtzman DM, Clements JD, Selkoe DJ, Duff KE.  Evidence for peripheral clearance of cerebral Aß protein following chronic, active Aß immunization in PSAPP mice.  Neurobiol. Dis., 2003; 14: 10-18.

LaVoie MJ, Selkoe DJ.  The Notch ligands, Jagged and Delta, are sequentially processed by a-secretase and presenilin/g-secretase and release signaling fragments.  J Biol Chem, 2003; 278: 34427-37.

Baulac S, LaVoie MJ, Kimberly WT, Strahle J, Wolfe MS, Selkoe DJ, Xia W.  Functional g-secretase  complex assembly in Golgi/trans-Golgi network: Interactions among presenilin, nicastrin, Aph1, Pen-2 and g-secretase  substrates.  Neurobiol. Dis., 2003; 14: 194-204.

LaVoie MJ, Fraering P, Ostaszewski BL, Ye W, Kimberly WT, Wolfe MS, Selkoe DJ.  Assembly of the g-secretase complex involves early formation of an intermediate sub-complex of Aph-1 and nicastrin.  J. Biol. Chem. 2003: 278: 37213-22.

Leissring MA, Lu A, Condron MM, Teplow DB, Stein S, Farris RW, Selkoe DJ.  Kinetics of amyloid ß-protein  degradation determined by novel fluorescence- and fluorescence polarizaton-based assays.  J Biol Chem, 2003; 278: 37314-20.

Monsonego A, Zota V, Karni A, Krieger JI, Bar-or A, Bitan G, Budson AE, Sperling R, Selkoe DJ, Weiner HL.  Increased T cell reactivity to amyloid ß-protein in older humans and patients with Alzheimer’s disease.  J Clin Invest, 2003; 12: 415-422..

Sharon R, Bar-Joseph I, Mirick GE, Serhan CN, Selkoe DJ.  Altered fatty acid composition of dopaminergic neurons expressing a-synuclein and human brains with a-synucleinopathies.  J. Biol. Chem. 2003; 278: 49874-49881.

Chyung J and Selkoe DJ.  Inhibition of receptor mediated endocytosis demonstrates generation of Aß at the cell surface.  J Biol Chem  2003; 278: 51035-51043.

Leissring MA, Farris RW, Chang AY, Wu X, Frosch MP, Selkoe DJ.  Enhanced proteolysis of ß-amyloid in APP transgenic mice prevents plaque formation, secondary pathology and premature death.  Neuron 2003; 40: 1087-1093.

Fraering P, LaVoie MA, Ye W, Ostazewski BL, Kimberly WT, Selkoe DJ, Wolfe MS.  Detergent-dependent dissociation of active g-secretase  reveals an interaction between Pen-2 and PS1-NTF and offers a model for subunit organization within the complex.  Biochem, 2004; 43: 323-333.

Farris RW, Mansourian S, Leissring MA, Eckman EA, Sun X, Bertram L, Eckman CB, Tanzi RE, Selkoe DJ.  Partial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid ß-protein. Am J Pathol.  2004; 164:1425-34.

Wang Q, Walsh DM, Rowan MJ, Selkoe DJ and Anwyl R. Block of LTP by naturally secreted and synthetic amyloid ß-peptide in hippocampal slices is mediated via activation of the kinases c-Jun N-terminal kinase,  Cdk5 and p38 MAP and metabotropic glutamate  receptor  type 5. J Neurosci,  2004; 24: 3370-3378.

Lemere CA, Beierschmitt A, Iglesias M, Spooner ET, Bloom JK, Leverone JF, Zheng JB, Seabrook TJ, Luoard D, Li D, Selkoe DJ, Palmour RM, Ervin FR.  Alzheimer’s Disease Aß Vaccine Reduces CNS Aß Levels in a Non-Human Primate, the Caribbean Vervet.  Am J Pathol  2004, 165: 283-297.

Hayashi H, Kimura N. Yamaguchi H, Hasegawa K, Yokoseki T, Shibata M, Yamamoto N, Michikawa M, Yoshikawa Y, Terao K, Matsuzaki K, Lemere CA, Selkoe DJ, Naiki H, Yanagisawa K.  A seed for Alzheimer amyloid in the brain.  J Neurosci, 2004; 24:4894-4902.

Fraering P, Ye W, Strub J-M, Dolios G, LaVoie MJ, Ostaszewski BL, van Dorselaer A, Wang R, Selkoe DJ, Wolfe MS.  Purification and characterization of the human g-secretase complex.  Biochemistry, 2004; 43: 9774-9789.

Ye C, Walsh DM, Selkoe DJ, Hartley DM. Amyloid beta-protein induced electrophysiological changes are dependent on aggregation state:  N-methyl-D-aspartate (NMDA) versus non_NMDA receotr/channel activation.  Neurosci Lett  2004; 19: 266-320-325.

Leissring MA, Farris W, Wu X, Christodoulou DC, Haigis MC, Guarente L, Selkoe DJ. Alternative translation initiation generates a novel isoform of insulin-degrading enzyme targeted to mitochondria. Biochem J  2004; 383, 439-46.

Klyubin I, Walsh, DM, Cullen WK, Fadeeva J, Anwyl R, Selkoe DJ, Rowan MJ.  Soluble Arctic amyloid ß-protein inhibits hippocampal long-term potentiation in vivo.  Euro J Neurosci 2004; 19: 2839-2846.

Cleary JP,  Walsh DM, Hofmeister JJ,  Shankar GM, Kuskowski MA, Selkoe DJ, Ashe KH.  Natural oligomers of the amyloid ß-protein specifically disrupt cognitive function.  Nat Neuroscience, 2005; 8:79-84. 

Chyung JH, Raper DM, Selkoe DJ.  Gamma-secretase exists on the plasma membrane as an intact complex that accepts substrates and effects intramembrane cleavage.  J Biol Chem,  2005; 280: 4383-4392.

Walsh DM, Townsend M, Podlisny MB, Shanker GM, Fadeeva JV, El-Agnaf O, Hartley DM, Selkoe DJ.  Certain inhibitors of synthetic Aß fibrillogenesis block oligomerization of natural Aß and thereby rescue long term potentiation.  J Neurosci, 2005; 25 2455-2462.

Farris RW, Leissring MA, Hemming ML, Chang AY, Selkoe DJ.  Alternative splicing of human insulin-degrading enzyme yields a novel isoform with decreased ability to degrade insulin and amyloid ß-protein, J Biol Chem, 2005; 44: 6513-6525.

Kluybin I, Walsh DM, Lemere CA, Cullen WK, Shankar GM, Betts V, Spooner ET, Jiang L, Anwyl R, Selkoe DJ, Rowan MJ.  Active and passive immunotherapy for Alzheimer’s disease: Direct neutralization in vivo of amyloid ß-protein oligomers that disrupt synaptic plasticity.  Nat Med. 2005;11:556-61. Epub 2005 Apr 17.

Kimberly WT, Zheng JB, Town T, Flavell RA, Selkoe DJ.  Physiological regulation of the ß-amyloid precursor protein signaling domain by c-Jun N-terminal kinase JNK3 during neuronal differentiation.  J Neurosci, 2005; 25: 5533-5534.

Hemming ML, Selkoe DJ.  Amyloid ß-protein is degraded by cellular angiotensin-converting enzyme (ACE) and elevated by ACE inhibitor.  J Biol Chem, 2005; 280: 37644-37650.

LaVoie M, Ostaszewski B, Weihofen A, Schlossmacher MG, Selkoe DJ.  Dopamine covalently modifies and functionally inactivates parkin.  Nat Med, 2005; 11: 1214-1221.

Fraering PC, Ye W, LaVoie MJ, Ostaszewski BL, Selkoe DJ, Wolfe MS.  g-secretase substrate selectivity can be modulated directly via interaction with a nucleotide binding site.  J Biol Chem, 2005; 23;280:41987-96.

Rechards M, Xia W. Oorschot V, van Dijk S, Annaert W, Selkoe DJ, Klumperman J.  Presenilin-1-mediated retention of APP-derivatives in early biosynthetic compartments.  Traffic, 2006; 7: 354-364.

Lazarov VK, Fraering PC, Chen Z, Ye W, Wolfe MS, Selkoe DJ.  Electron microscopic structure of purified, active a-secretase reveals an aqueous intramembrane chamber and two pores.  Proc Natl Acad Sci USA, 2006;103(18):6889-94. Epub 2006 Apr 24.

Farris W, Schutz SG, Cirrito JR, Shankar GM, Sun X, George A, Leissring MA, Walsh DM, Qiu WQ, Holtzman DM, Selkoe DJ. Abstract Loss of neprilysin function promotes amyloid plaque formation and causes cerebral amyloid angiopathy. Am J Pathol. 2007 Jul;171(1):241-51. Pubmed Link

Farris W, Schutz SG, Cirrito JR, Shankar GM, Sun X, George A, Leissring MA, Walsh DM, Qiu WQ, Holtzman DM, Selkoe DJ. Loss of Neprilysin Function Promotes Amyloid Plaque Formation and Causes Cerebral Amyloid Angiopathy. Am J Pathol. 2007 May 18;

Walsh DM, Minogue AM, Sala Frigerio C, Fadeeva JV, Wasco W, Selkoe DJ. The APP family of proteins: similarities and differences. Biochem Soc Trans. 2007 Apr;35(Pt 2):416-20.

Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL. Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci. 2007 Mar 14;27(11):2866-75.

Hemming ML, Selkoe DJ, Farris W. Effects of prolonged angiotensin-converting enzyme inhibitor treatment on amyloid beta-protein metabolism in mouse models of Alzheimer disease.Neurobiol Dis. 2007 Apr;26(1):273-81.

Chen AC, Selkoe DJ. Response to: Pardossi-Piquard et al., "Presenilin-Dependent Transcriptional Control of the Abeta-Degrading Enzyme Neprilysin by Intracellular Domains of betaAPP and APLP." Neuron 46, 541-554. Neuron. 2007 Feb 15;53(4):479-83.

Walsh DM, Selkoe DJ. A beta oligomers - a decade of discovery. J Neurochem. 2007 Jun;101(5):1172-84.

Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol. 2007 Feb;8(2):101-12. Review.

Kim M, Hersh LB, Leissring MA, Ingelsson M, Matsui T, Farris W, Lu A, Hyman BT, Selkoe DJ, Bertram L, Tanzi RE. Decreased catalytic activity of the insulin-degrading enzyme in chromosome 10-linked Alzheimer disease families.
J Biol Chem. 2007 Mar 16;282(11):7825-32. Epub 2007 Jan 22.

Townsend M, Cleary JP, Mehta T, Hofmeister J, Lesne S, O'Hare E, Walsh DM, Selkoe DJ.
Orally available compound prevents deficits in memory caused by the Alzheimer amyloid-beta oligomers. Ann Neurol. 2006 Dec;60(6):668-76.

Qiu WQ, Sun X, Selkoe DJ, Mwamburi DM, Huang T, Bhadela R, Bergethon P, Scott TM, Summergrad P, Wang L, Rosenberg I, Folstein M.  Depression is associated with low plasma Abeta42 independently of cardiovascular disease in the homebound elderly. Int J Geriatr Psychiatry. 2007 Jun;22(6):536-42.