The grant detail shows the name of the PI, active dates of the project, the funding institute and the abstract of the grant. This abstract is what is used to create the fingerprint of the grant. If any publications referencing this grant are found in the data, they will be listed here as well.
Protein-Protein Interactions in the Biology of Beta-APP
1 January 1995 - 31 August 2013
NATIONAL INSTITUTE ON AGING
Total Funding: $ 5,559,857
[unreadable] Studies from many laboratories now generally support the amyloid (or Abeta) hypothesis of Alzheimer's disease (AD), and therapeutic trails based on this concept have begun. Nevertheless, we are left with many unresolved and fascinating biological questions about how a small hydrophobic peptide slowly accumulates in the brain with age and can apparently initiate cytopathology. Perhaps foremost among these questions is exactly why cerebral Abeta levels are elevated in humans who develop AD. Increased Abeta production appears to explain only a small minority of cases, principally those inheriting mutations in APP or the presenilins. This realization suggests that many, perhaps most, cases of AD are caused by faulty clearance of a peptide that is produced at normal levels throughout life. Our proposed work here is based on 3 related hypotheses: 1) defects in proteases which degrade Abeta may underlie some or many cases of familial and sporadic late-onset AD;2) non-proteolytic clearance mechanisms (e.g., receptor-mediated efflux through the blood brain barrier) could explain the rise in cerebral Abeta in other cases;and 3) whether or not these two mechanisms are actually causative, subtly activating such proteases or else stimulating protein transport mechanisms could lower cerebral Abeta levels therapeutically. To extend our productive work under this grant on both the basic and applied aspects of this understudied subject, we propose 3 aims: Aim 1: To determine whether central or peripheral expression of engineered versions of two well-characterized Abeta degrading proteases - neprilysin and insulin degrading enzyme (IDE) -can safely and effectively decrease cerebral Abeta burden in mouse models of AD. Aim 2: In view of the recent unequivocal demonstration that IDE exists normally on the plasma membrane (namely, as the receptor for varicella-zoster virus), to further ellucidate the unusual cell biology and membrane trafficking of IDE that enables it to be involved in the degradation of both extracellular/intraluminal substrates (e.g., Abeta, insulin, amylin) and cytoplasmic substrates (e.g., AICD). Aim 3: To pursue a recently initiated project that addresses an even less well-studied aspect of Abeta clearance than proteolysis, namely, to rigorously identify and validate the cell- surface receptors capable of mediating the efflux of soluble Abeta across the BBB, using both in vitro and in vivo models. Understanding how both proteolysis and non-proteolytic clearance regulate Abeta levels in the brain has major implications for both the genesis and treatment of this complex disorder. At the same time, the proposed experiments have fundamental implications for peptide turnover in the mammalian brain and for the cell biology of metalloproteases. Many scientists now support the idea that the gradual buildup of a small protein, amyloid beta-protein (Abeta), in brain regions serving memory and thinking causes Alzheimer's disease. This grant will examine exactly why this buildup occurs over time, focusing on two potential problems: 1) faulty cutting up of the Abeta protein in the brain;or 2) faulty transport of the Abeta protein from the brain into the circulation. We will also explore new ways to increase the cutting up or the transport of Abeta as future therapeutic approaches for preventing Alzheimer's disease. [unreadable] [unreadable]
49 Resulting Publications
Ting Yang; Soyon Hong; Tiernan O'Malley; Reisa A Sperling; Dominic M Walsh; Dennis J SelkoeAlzheimer's & dementia : the journal of the Alzheimer's Association 2013;9(2):99-112.
Oliver Holmes; Swetha Paturi; Wenjuan Ye; Michael S Wolfe; Dennis J SelkoeBiochemistry 2012;51(17):3565-75.
Soyon Hong; Omar Quintero-Monzon; Beth L Ostaszewski; Daniel R Podlisny; William T Cavanaugh; Ting Yang; David M Holtzman; John R Cirrito; Dennis J SelkoeThe Journal of neuroscience : the official journal of the Society for Neuroscience 2011;31(44):15861-9.
Cathrin Meissner; Holger Lorenz; Andreas Weihofen; Dennis J Selkoe; Marius K LembergJournal of neurochemistry 2011;117(5):856-67.
Carlo Sala Frigerio; Julia V Fadeeva; Aedín M Minogue; Martin Citron; Fred Van Leuven; Matthias Staufenbiel; Paolo Paganetti; Dennis J Selkoe; Dominic M WalshThe FEBS journal 2010;277(6):1503-18.
Ira Espuny-Camacho; Diana Dominguez; Pascal Merchiers; Luc Van Rompaey; Dennis Selkoe; Bart De StrooperJournal of Alzheimer's disease : JAD 2010;20(4):1119-32.
Malcolm A Leissring; Enrico Malito; Sabrine Hedouin; Lael Reinstatler; Tomoko Sahara; Samer O Abdul-Hay; Shakeel Choudhry; Ghulam M Maharvi; Abdul H Fauq; Malwina Huzarska; et al.PloS one 2010;5(5):e10504.
Christelle Cabrol; Malwina A Huzarska; Christopher Dinolfo; Maria C Rodriguez; Lael Reinstatler; Jake Ni; Li-An Yeh; Gregory D Cuny; Ross L Stein; Dennis J Selkoe; et al.PloS one 2009;4(4):e5274.
Matthew L Hemming; Joshua E Elias; Steven P Gygi; Dennis J SelkoePloS one 2009;4(12):e8477.
Marie Neant-Fery; Rubén D Garcia-Ordoñez; Todd P Logan; Dennis J Selkoe; Lilin Li; Lael Reinstatler; Malcolm A LeissringProceedings of the National Academy of Sciences of the United States of America 2008;105(28):9582-7.
Matthew L Hemming; Michaela Patterson; Casper Reske-Nielsen; Ling Lin; Ole Isacson; Dennis J SelkoePLoS medicine 2007;4(8):e262.
Wesley Farris; Sonja G Schütz; John R Cirrito; Ganesh M Shankar; Xiaoyan Sun; Ana George; Malcolm A Leissring; Dominic M Walsh; Wei Qiao Qiu; David M Holtzman; et al.The American journal of pathology 2007;171(1):241-51.
Matthew L Hemming; Dennis J Selkoe; Wesley FarrisNeurobiology of disease 2007;26(1):273-81.
Matthew L Hemming; Dennis J SelkoeThe Journal of biological chemistry 2005;280(45):37644-50.
Wesley Farris; Malcolm A Leissring; Matthew L Hemming; Alice Y Chang; Dennis J SelkoeBiochemistry 2005;44(17):6513-25.
Malcolm A Leissring; Wesley Farris; Xining Wu; Danos C Christodoulou; Marcia C Haigis; Leonard Guarente; Dennis J SelkoeThe Biochemical journal 2004;383(Pt. 3):439-46.
Malcolm A Leissring; Wesley Farris; Alice Y Chang; Dominic M Walsh; Xining Wu; Xiaoyan Sun; Matthew P Frosch; Dennis J SelkoeNeuron 2003;40(6):1087-93.
W Taylor Kimberly; William P Esler; Wenjuan Ye; Beth L Ostaszewski; Jun Gao; Thekla Diehl; Dennis J Selkoe; Michael S WolfeBiochemistry 2003;42(1):137-44.
W Taylor Kimberly; Matthew J LaVoie; Beth L Ostaszewski; Wenjuan Ye; Michael S Wolfe; Dennis J SelkoeThe Journal of biological chemistry 2002;277(38):35113-7.
William P Esler; W Taylor Kimberly; Beth L Ostaszewski; Wenjuan Ye; Thekla S Diehl; Dennis J Selkoe; Michael S WolfeProceedings of the National Academy of Sciences of the United States of America 2002;99(5):2720-5.
C L Moore; D D Leatherwood; T S Diehl; D J Selkoe; M S WolfeJournal of medicinal chemistry 2000;43(18):3434-42.
W P Esler; W T Kimberly; B L Ostaszewski; T S Diehl; C L Moore; J Y Tsai; T Rahmati; W Xia; D J Selkoe; M S WolfeNature cell biology 2000;2(7):428-34.
K Vekrellis; Z Ye; W Q Qiu; D Walsh; D Hartley; V Chesneau; M R Rosner; D J SelkoeThe Journal of neuroscience : the official journal of the Society for Neuroscience 2000;20(5):1657-65.
C L Moore; T S Diehl; D J Selkoe; M S WolfeAnnals of the New York Academy of Sciences 2000;920():197-205.
D M Hartley; D M Walsh; C P Ye; T Diehl; S Vasquez; P M Vassilev; D B Teplow; D J SelkoeThe Journal of neuroscience : the official journal of the Society for Neuroscience 1999;19(20):8876-84.
D M Walsh; D M Hartley; Y Kusumoto; Y Fezoui; M M Condron; A Lomakin; G B Benedek; D J Selkoe; D B TeplowThe Journal of biological chemistry 1999;274(36):25945-52.
J F Poduslo; G L Curran; B Sanyal; D J SelkoeNeurobiology of disease 1999;6(3):190-9.
M S Wolfe; W Xia; C L Moore; D D Leatherwood; B Ostaszewski; T Rahmati; I O Donkor; D J SelkoeBiochemistry 1999;38(15):4720-7.
W Q Qiu; D M Walsh; Z Ye; K Vekrellis; J Zhang; M B Podlisny; M R Rosner; A Safavi; L B Hersh; D J SelkoeThe Journal of biological chemistry 1998;273(49):32730-8.
M Citron; C B Eckman; T S Diehl; C Corcoran; B L Ostaszewski; W Xia; G Levesque; P St George Hyslop; S G Younkin; D J SelkoeNeurobiology of disease 1998;5(2):107-16.
M B Podlisny; D M Walsh; P Amarante; B L Ostaszewski; E R Stimson; J E Maggio; D B Teplow; D J SelkoeBiochemistry 1998;37(11):3602-11.
M S Wolfe; M Citron; T S Diehl; W Xia; I O Donkor; D J SelkoeJournal of medicinal chemistry 1998;41(1):6-9.
D J Watson; A D Lander; D J SelkoeThe Journal of biological chemistry 1997;272(50):31617-24.
W Xia; J Zhang; R Perez; E H Koo; D J SelkoeProceedings of the National Academy of Sciences of the United States of America 1997;94(15):8208-13.
J Walter; J Grünberg; A Capell; B Pesold; A Schindzielorz; M Citron; K Mendla; P S George-Hyslop; G Multhaup; D J Selkoe; et al.Proceedings of the National Academy of Sciences of the United States of America 1997;94(10):5349-54.
W Q Qiu; Z Ye; D Kholodenko; P Seubert; D J SelkoeThe Journal of biological chemistry 1997;272(10):6641-6.
J Walter; A Capell; A Y Hung; H Langen; M Schnölzer; G Thinakaran; S S Sisodia; D J Selkoe; C HaassThe Journal of biological chemistry 1997;272(3):1896-903.
M Citron; D Westaway; W Xia; G Carlson; T Diehl; G Levesque; K Johnson-Wood; M Lee; P Seubert; A Davis; et al.Nature medicine 1997;3(1):67-72.
M B Podlisny; M Citron; P Amarante; R Sherrington; W Xia; J Zhang; T Diehl; G Levesque; P Fraser; C Haass; et al.Neurobiology of disease 1997;3(4):325-37.
J F Poduslo; G L Curran; J J Haggard; A L Biere; D J SelkoeNeurobiology of disease 1997;4(1):27-34.
A L Biere; B Ostaszewski; E R Stimson; B T Hyman; J E Maggio; D J SelkoeThe Journal of biological chemistry 1996;271(51):32916-22.
M Citron; T S Diehl; G Gordon; A L Biere; P Seubert; D J SelkoeProceedings of the National Academy of Sciences of the United States of America 1996;93(23):13170-5.
J Walter; A Capell; J Grünberg; B Pesold; A Schindzielorz; R Prior; M B Podlisny; P Fraser; P S Hyslop; D J Selkoe; et al.Molecular medicine (Cambridge, Mass.) 1996;2(6):673-91.
M Citron; T S Diehl; A Capell; C Haass; D B Teplow; D J SelkoeNeuron 1996;17(1):171-9.
W Q Qiu; W Borth; Z Ye; C Haass; D B Teplow; D J SelkoeThe Journal of biological chemistry 1996;271(14):8443-51.
C A Lemere; J K Blusztajn; H Yamaguchi; T Wisniewski; T C Saido; D J SelkoeNeurobiology of disease 1996;3(1):16-32.
D J SelkoeCold Spring Harbor symposia on quantitative biology 1996;61():587-96.
C Haass; C A Lemere; A Capell; M Citron; P Seubert; D Schenk; L Lannfelt; D J SelkoeNature medicine 1995;1(12):1291-6.
A L Biere; B Ostaszewski; H Zhao; S Gillespie; S G Younkin; D J SelkoeNeurobiology of disease 1995;2(3):177-87.
This section shows information that has been computed by using the fingerprint of the grant, including related publications, related experts and related grants - all with fingerprints representing significant amounts of overlap between their fingerprint and this grant. The red dots indicate whether those experts or terms actually appear within this grant, showing potential and actual connections.
Appears in this Publication
Author of this Publication