BBS Faculty Member - Dennis Selkoe

Dennis Selkoe

Vincent and Stella Coates Professor of Neurologic Diseases, HMS
Co-Director, Ann Romney Center for Neurologic Diseases, Dept of Neurology, BWH

Brigham and Women's Hospital
Building for Transformative Medicine, 10th Floor
60 Fenwood Road
Boston, MA 02115
Tel: 617-525-5260
Fax: 617-525-5200
Email: dselkoe@partners.org
Visit my lab page here.



Our laboratory is interested in the biochemistry and molecular and cell biology of neuronal degeneration during aging of the mammalian brain, particularly in Alzheimer’s (AD) and Parkinson’s (PD) diseases. The laboratory originally developed methods for the purification and analysis of the intraneuronal paired helical filaments and extracellular amyloid fibrils that are the hallmarks of the neuropathology of AD. Extensive studies of the trafficking and processing of the β-amyloid precursor protein (APP), a type 1 integral membrane glycoprotein critically involved in AD, have been undertaken and continue. The laboratory discovered that Aβ is normally produced from APP throughout life, enabling dynamic cell biological studies of the mechanism of Aβ production and its pharmacological inhibition. The function of APP and the toxic properties of various Aβ assemblies on cultured neurons and in relevant mouse models are being examined. The identification of presenilin as the active site of γ-secretase and its role in APP and Notch signaling functions are also under study. Finally, a similar approach is being applied to the function and dysfunction of gene products implicated in PD, particularly alpha-synuclein. A wide range of methods is employed, including cell culture, protein biochemistry, molecular biology, immunohistochemistry, light and electron microscopy, electrophysiology and animal modeling.



Last Update: 12/8/2016



Publications

For a complete listing of publications click here.

 


 

Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Selkoe DJ. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature 1999; 398: 513-517.

Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smth I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabataini L, Selkoe DJ. Amyloid ß-protein dimers isolated directly from Alzheimer brains impair synaptic plasticity and memory.
Nat Med, 2008; 14: 837-842. PMCID: PMC2772133

Bartels T, Choi JG, Selkoe DJ.
a-synuclein exists normally in cells and brain as a natively folded tetramer that resists aggregation compared to unfolded monomers. Nature, 2011 Aug 14;477(7362):107-10.

Li S, Jin M, Zhang D, Yang T, Koeglsperger T, Fu H, Selkoe DJ. Environmental novelty potently prevents impairment of hippocampal synaptic plasticity by human Aβ oligomers via a β2-adrenergic signaling pathway.
Neuron, 2013; Mar 6;77(5):929-41.

Dettmer U, Newman AJ, Soldner F, Luth ES, Kim NC, Bartels T, Jaenisch R, Selkoe DJ. Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation.
Nat Commun, 2015 Jun 16;6:7314. Free PMC article.

Chen AC, Kim S, Shepardson N, Patel S, Hong S, Selkoe DJ.  Physical and functional interaction between the α- and γ-secretases: A new model of regulated intramembrane proteolysis. 
J Cell Biol. 2015 Dec 21;211(6):1157-76. 



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