The FASEB Journal, Vol 9, 366-370, Copyright © 1995 by The Federation of American Societies for Experimental Biology

REVIEWS

Role of the beta-amyloid protein in Alzheimer's disease

SS Sisodia and DL Price
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.

A major histopathological hallmark of Alzheimer's disease (AD) is the presence of amyloid deposits in the parenchyma of the amygdala, hippocampus, and neocortex. The principal component of amyloid is the beta-amyloid protein (A beta), a 39-43 amino acid peptide composed of a portion of the transmembrane domain and the extracellular domain of the amyloid precursor protein (APP). APP occurs as several A beta- containing isoforms of 695, 751, and 770 amino acids, with the latter two APP containing a domain that shares structural and functional homologies with Kunitz serine protease inhibitors. In cultured cells, APP mature through the constitutive secretory pathway, and some cell surface-bound APP are cleaved by an enzyme, designated as alpha- secretase, within the A beta domain, an event that precludes A beta amyloidogenesis. Several studies have delineated two additional pathways of APP processing: first, an endosomal/lysosomal pathway generates a complex set of APP-related membrane-bound fragments, some of which contain the entire A beta sequence; and, second, by mechanisms which are not fully understood, A beta 1-40 is secreted into the conditioned medium in vitro and is present in cerebrospinal fluid in vivo. The intracellular sites of enzymes responsible for proteolytic cleavage at the NH2 and COOH termini of A beta, termed gamma- and beta- secretase, respectively, have not been identified. Finally, recent molecular genetic investigations have identified a variety of mutations in APP that segregate with early-onset familial AD and with hereditary cerebral hemorrhage with amyloid, Dutch type (HCHWA-D). Several of these mutations appear to influence APP processing and result in the production of higher levels or longer A beta-related peptides that are inherently more fibrillogenic. Although a variety of lines of evidence implicates APP/A beta in AD, the mechanisms by which A beta influences the biology and vulnerability of neural cells are not fully understood but are very active areas of investigation. This review focuses on the present state of our understanding of APP and A beta in the context of AD.

This article has been cited by other articles:

				G. Mamikonyan, M. Necula, M. Mkrtichyan, A. Ghochikyan, I. Petrushina, N. Movsesyan, E. Mina, A. Kiyatkin, C. G. Glabe, D. H. Cribbs, et al. Anti-Abeta1 11 Antibody Binds to Different beta-Amyloid Species, Inhibits Fibril Formation, and Disaggregates Preformed Fibrils but Not the Most Toxic Oligomers J. Biol. Chem., August 3, 2007; 282(31): 22376 - 22386. [Abstract] [Full Text] [PDF]

				X. Wang and J. Robbins Heart Failure and Protein Quality Control Circ. Res., December 8, 2006; 99(12): 1315 - 1328. [Abstract] [Full Text] [PDF]

				M. T. Maloney, L. S. Minamide, A. W. Kinley, J. A. Boyle, and J. R. Bamburg {beta}-Secretase-Cleaved Amyloid Precursor Protein Accumulates at Actin Inclusions Induced in Neurons by Stress or Amyloid {beta}: A Feedforward Mechanism for Alzheimer's Disease J. Neurosci., December 7, 2005; 25(49): 11313 - 11321. [Abstract] [Full Text] [PDF]

				T. J. Dickerson and K. D. Janda Glycation of the amyloid {beta}-protein by a nicotine metabolite: A fortuitous chemical dynamic between smoking and Alzheimer's disease PNAS, July 8, 2003; 100(14): 8182 - 8187. [Abstract] [Full Text] [PDF]

				H. Sato, M. Tamba, S. Okuno, K. Sato, K. Keino-Masu, M. Masu, and S. Bannai Distribution of Cystine/Glutamate Exchange Transporter, System xc-, in the Mouse Brain J. Neurosci., September 15, 2002; 22(18): 8028 - 8033. [Abstract] [Full Text] [PDF]

				J. M. Mettenburg, D. J. Webb, and S. L. Gonias Distinct Binding Sites in the Structure of alpha 2-Macroglobulin Mediate the Interaction with beta -Amyloid Peptide and Growth Factors J. Biol. Chem., April 5, 2002; 277(15): 13338 - 13345. [Abstract] [Full Text] [PDF]

				X.-F. Li, G. Thinakaran, S. S. Sisodia, and F.-S. X. Yu Amyloid Precursor-like Protein 2 Promotes Cell Migration toward Fibronectin and Collagen IV J. Biol. Chem., September 17, 1999; 274(38): 27249 - 27256. [Abstract] [Full Text] [PDF]

				S. Du Yan, Y. Shi, A. Zhu, J. Fu, H. Zhu, Y. Zhu, L. Gibson, E. Stern, K. Collison, F. Al-Mohanna, et al. Role of ERAB/L-3-Hydroxyacyl-coenzyme A Dehydrogenase Type II Activity in Abeta -induced Cytotoxicity J. Biol. Chem., January 22, 1999; 274(4): 2145 - 2156. [Abstract] [Full Text] [PDF]

				S. K. Rhee, A. P. Quist, and R. Lal Amyloid beta  Protein-(1-42) Forms Calcium-permeable, Zn2+-sensitive Channel J. Biol. Chem., May 29, 1998; 273(22): 13379 - 13382. [Abstract] [Full Text] [PDF]

				M. P. Lambert, A. K. Barlow, B. A. Chromy, C. Edwards, R. Freed, M. Liosatos, T. E. Morgan, I. Rozovsky, B. Trommer, K. L. Viola, et al. Diffusible, nonfibrillar ligands derived from Abeta 1-42 are potent central nervous system neurotoxins PNAS, May 26, 1998; 95(11): 6448 - 6453. [Abstract] [Full Text] [PDF]

				C. U. Pietrzik, J. Hoffmann, K. Stober, C.-Y. Chen, C. Bauer, D. A. C. Otero, J.-M. Roch, and V. Herzog From differentiation to proliferation: The secretory amyloid precursor protein as a local mediator of growth in thyroid epithelial cells PNAS, February 17, 1998; 95(4): 1770 - 1775. [Abstract] [Full Text] [PDF]

				M. S. Forman, D. G. Cook, S. Leight, R. W. Doms, and V. M.-Y. Lee Differential Effects of the Swedish Mutant Amyloid Precursor Protein on beta -Amyloid Accumulation and Secretion in Neurons and Nonneuronal Cells J. Biol. Chem., December 19, 1997; 272(51): 32247 - 32253. [Abstract] [Full Text] [PDF]

				A. Kato, A. Fukunari, Y. Sakai, and T. Nakajima Prevention of Amyloid-Like Deposition by a Selective Prolyl Endopeptidase Inhibitor, Y-29794, in Senescence-Accelerated Mouse J. Pharmacol. Exp. Ther., October 1, 1997; 283(1): 328 - 335. [Abstract] [Full Text]

				A. F. Ikin, W. G. Annaert, K. Takei, P. De Camilli, R. Jahn, P. Greengard, and J. D. Buxbaum Alzheimer Amyloid Protein Precursor Is Localized in Nerve Terminal Preparations to Rab5-containing Vesicular Organelles Distinct from Those Implicated in the Synaptic Vesicle Pathway J. Biol. Chem., December 13, 1996; 271(50): 31783 - 31786. [Abstract] [Full Text] [PDF]

				F. Desdouits, J. D. Buxbaum, J. Desdouits-Magnen, AngusC. Nairn, and P. Greengard Amyloid beta Peptide Formation in Cell-free Preparations. REGULATION BY PROTEIN KINASE C, CALMODULIN, AND CALCINEURIN J. Biol. Chem., October 4, 1996; 271(40): 24670 - 24674. [Abstract] [Full Text] [PDF]

				J. Arribas, L. Coodly, P. Vollmer, T. K. Kishimoto, S. Rose-John, and J. Massagué Diverse Cell Surface Protein Ectodomains Are Shed by a System Sensitive to Metalloprotease Inhibitors J. Biol. Chem., May 10, 1996; 271(19): 11376 - 11382. [Abstract] [Full Text] [PDF]

				I. Pinnix, U. Musunuru, H. Tun, A. Sridharan, T. Golde, C. Eckman, C. Ziani-Cherif, L. Onstead, and K. Sambamurti A Novel gamma -Secretase Assay Based on Detection of the Putative C-terminal Fragment-gamma of Amyloid beta Protein Precursor J. Biol. Chem., January 5, 2001; 276(1): 481 - 487. [Abstract] [Full Text] [PDF]

				W. A. Maltese, S. Wilson, Y. Tan, S. Suomensaari, S. Sinha, R. Barbour, and L. McConlogue Retention of the Alzheimer's Amyloid Precursor Fragment C99 in the Endoplasmic Reticulum Prevents Formation of Amyloid beta -Peptide J. Biol. Chem., June 1, 2001; 276(23): 20267 - 20279. [Abstract] [Full Text] [PDF]