Hamdan Medical Journal (previously the Journal of Medical Sciences)

Table of Contents  

Unraveling the Molecular Basis of Alzheimer's Disease Yields Novel Therapies: A Personal Retrospective

Dennis J Selkoe
Published in : Journal of Medical Sciences ; Vol 2, No 3 (2009)
DOI : 10.2174/1996327000902030098

Abstract


Among the myriad disorders that can devastate mental function, the example of Alzheimer's disease looms particularly large for neuroscientists. In part, this is because it is the most common of the brain degenerative diseases. But it is also because it begins with a remarkably pure impairment of cognitive function. Patients with Alzheimer's disease are robbed insidiously of their most human qualities: memory, reasoning, abstraction, insight and language. In the beginning, otherwise healthy individuals experience a subtle and intermittent impairment of their ability to encode new memories, first of trivial and later important episodes of everyday life. The gradual dissolution of the ability to register new details and then retrieve them when needed evolves in an individual whose motor and sensory functions are well preserved. Over a span of many months to several years, first declarative and then nondeclarative memory are eroded, and other complex mental functions such as judgment and planning slowly slip away. But the subtlety of the earliest amnestic symptoms, occurring without clinical evidence of other neural dysfunction, suggest that something is discretely, perhaps intermittently, interrupting the function of synapses that encode new declarative memories. Research conducted over more than two decades suggests that this "something" is the amyloid β-protein (Aβ), a small, hydrophobic peptide with an ominous tendency to assemble into long-lived polymers in regions of the brain that serve memory and cognition. This chapter provides a personal retrospective of work in the author’s laboratory that contributed to this conclusion.



View article in  :   PDF    

References


Alzheimer A. Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Z Psychiatrie Psychisch- Gerichtliche Med 1907; 64: 146-8.

Shelanski ML, Wisniewski H, Terry RD. Preliminary isolation and fine structure analysis of the Alzheimer neurofilament. J Neuropathol Exp Neurol 1971; 30(1): 146-7.

Selkoe DJ, Ihara Y, Salazar FJ. Alzheimer's disease: insolubility of partially purified paired helical filaments in sodium dodecyl sulfate and urea. Science 1982; 215: 1243-5.

Ihara Y, Abraham C, Selkoe DJ..Antibodies to paired helical filaments in Alzheimer's disease do not recognize normal brain proteins. Nature 1983; 304: 727-30.

Kosik KS, Joachim CL, Selkoe DJ. Microtubuleassociated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc Natl Acad Sci USA 1986; 83: 4044-8.

Nukina N, Ihara Y. One of the antigenic determinants of paired helical filaments is related to tau protein. J Biochem 1986; 99(5): 1541-4.

Ihara Y, Nukina N, Miura R, Ogawara M. Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer's disease. J Biochem 1986; 99(6): 1807-10.

Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 1986; 83(13): 4913-7.

Iqbal K, Grundke-Iqbal I, Zaidi T, Ali N, Wisniewski HM. Are Alzheimer neurofibrillary tangles insoluble polymers? Life Sci 1986; 38(18): 1695-700.

Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem 1986; 261(13): 6084-9.

Glenner GG, Wong CW. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984; 120(3): 885-90.

Glenner GG, Wong CW, Quaranta V, Eanes ED. The amyloid deposits in Alzheimer's disease: their nature and pathogenesis. Appl Pathol 1984; 2(6): 357-69.

Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA 1985; 82: 4245-9.

Selkoe DJ, Abraham CR, Podlisny MB, Duffy LK. Isolation of low-molecular-weight proteins from amyloid plaque fibers in Alzheimer's disease. J Neurochem 1986; 46: 1820-34.

Kirschner DA, Abraham C, Selkoe DJ. X-ray diffraction from intraneuronal paired helical filaments and extraneuronal amyloid fibers in Alzheimer's disease indicates cross-beta conformation. Proc Natl Acad Sci USA 1986; 83: 503-7.

Kirschner DA, Inouye H, Duffy LK, Sinclair A, Lind M, Selkoe DJ. Synthetic peptide homologous to beta protein from Alzheimer disease forms amyloid-like fibrils in vitro. Proc Natl Acad Sci USA 1987; 84: 6953-7.

Selkoe DJ, Podlisny MB, Joachim CL, et al. Betaamyloid precursor protein of Alzheimer disease occurs as 110- to 135-kilodalton membrane-associated proteins in neural and nonneural tissues. Proc Natl Acad Sci USA 1988; 85: 7341-5.

Haass C, Schlossmacher MG, Hung AY, et al. Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature 1992; 359(6393): 322-5.

Schlossmacher MG, Ostaszewski BL, Hecker LI, et al. Detection of distinct isoform patterns of the betaamyloid precursor protein in human platelets and lymphocytes. Neurobiol Aging 1992; 13(3): 421-34.

Seubert P, Vigo-Pelfrey C, Esch F, et al. Isolation and quantification of soluble Alzheimer's beta-peptide from biological fluids. Nature 1992; 359(6393): 325-7.

Younkin SG. Processing of the Alzheimer's disease beta A4 amyloid protein precursor (APP). Brain Pathol 1991; 1(4): 253-62.

Selkoe DJ. Physiological production of the betaamyloid protein and the mechanism of Alzheimer's disease. Trends Neurosci 1993; 16: 403-9.

Mullan M, Crawford F, Axelman K, et al. A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet 1992; 1:345-7.

Citron M, Oltersdorf T, Haass C, et al. Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature 1992; 360: 672-4.

Citron M, Vigo-Pelfrey C, Teplow DB, et al. Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation. Proc Natl Acad Sci USA 1994 ; 91: 11993-7.

St George-Hyslop P, Haines J, Rogaev E, et al. Genetic evidence for a novel familial Alzheimer's disease locus on chromosome 14. Nat Genet 1992; 2: 330-4.

Jarrett JT, Lansbury PT Jr. Seeding "one-dimensional crystallization" of amyloid: a pathogenic mechanism in Alzheimer's disease and scrapie? Cell 1993; 73: 1055- 8.

Xia W, Zhang J, Perez R, Koo EH, Selkoe DJ. Interaction between amyloid precursor protein and presenilins in mammalian cells: implications for the pathogenesis of Alzheimer disease. Proc Natl Acad Sci USA 1997; 94: 8208-13.

Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ. Two transmembrane aspartates in presenilin- 1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 1999; 398: 513-7.

De Strooper B, Saftig P, Craessaerts K, et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 1998; 391(6665): 387-90.

Struhl G, Greenwald I. Presenilin-mediated transmembrane cleavage is required for Notch signal transduction in Drosophila. Proc Natl Acad Sci USA 2001; 98(1): 229-34.

Ray WJ, Yao M, Mumm J, et al. Cell surface presenilin- 1 participates in the gamma-secretase-like proteolysis of Notch. J Biol Chem 1999; 274(51): 36801-7.

De Strooper B, Annaert W, Cupers P, et al. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 1999; 398(6727): 518-22.

Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ.Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc Natl Acad Sci USA. 2003; 100: 6382-7.

Qiu WQ, Walsh DM, Ye Z, et al. Insulin-degrading enzyme regulates extracellular levels of amyloid betaprotein by degradation. J Biol Chem 1998; 273: 32730- 8.

Bertram L, Blacker D, Mullin K, et al. Evidence for genetic linkage of Alzheimer's disease to chromosome 10q. Science 2000; 290: 2302-3.

Farris W, Mansourian S, Chang Y, et al. (2003). Insulindegrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci USA 2003; 100: 4162-7.

Leissring MA, Farris W, Chang AY, et al. Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron 2003; 40: 1087-93.

Podlisny MB, Ostaszewski BL, Squazzo SL, et al. Aggregation of secreted amyloid beta-protein into sodium dodecyl sulfate-stable oligomers in cell culture. J Biol Chem 1995; 270: 9564-70.

Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002; 416: 535-9.

Cleary JP, Walsh DM, Hofmeister JJ, et al. Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat Neurosci 2005; 8: 79-84.





Add comment 





Home  Editorial Board  Search  Current Issue  Archive Issues  Announcements  Aims & Scope  About the Journal  How to Submit  Contact Us
Find out how to become a part of the HMJ  |   CLICK HERE >>
© Copyright 2012 - 2013 HMJ - HAMDAN Medical Journal. All Rights Reserved         Website Developed By Cedar Solutions INDIA