Alzheimer's disease: inside, outside, upside down.

Neurotoxicity of beta-amyloid peptide (A beta) in Alzheimer's disease (AD) is usually thought to arise from the nonspecific effects of high concentrations of A beta on vulnerable neurons, resulting in membrane destabilization and increasing intracellular calcium concentration. This review advances the hypothesis that at early stages of AD, when A beta is present in lower amounts, its ability to perturb the function of cellular targets is mediated by specific cofactors present on the cell surface and intracellularly. Receptor for advanced glycation endproducts (RAGE) is a cell-surface receptor which binds A beta and amplifies its effects on cells in the nanomolar range. The intracellular enzyme A beta-binding alcohol dehydrogenase (ABAD) is likely to engage nascent A beta formed in the endoplasmic reticulum, and to mediate cell stress from this site. The analysis of A beta interaction with RAGE and ABAD, as well as other cofactors, provides insight into new mechanisms and, potentially, identifies therapeutic targets relevant to neuronal dysfunction in AD.

[1]  R. Doms,et al.  Alzheimer's Aβ(1–42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells , 1997, Nature Medicine.

[2]  C. Masters,et al.  Distinct sites of intracellular production for Alzheimer's disease Aβ40/42 amyloid peptides , 1997, Nature Medicine.

[3]  D. Schubert,et al.  Beta amyloid toxicity does not require RAGE protein. , 1997, Biochemical and biophysical research communications.

[4]  C. Kawas,et al.  Neuronal cell death in Alzheimer's disease correlates with apoE uptake and intracellular Abeta stabilization. , 1997, The Journal of clinical investigation.

[5]  J. Trojanowski,et al.  Monoclonal antibodies to a 100-kd protein reveal abundant A beta-negative plaques throughout gray matter of Alzheimer's disease brains. , 1997, The American journal of pathology.

[6]  Y. Ihara,et al.  Intracellular Generation and Accumulation of Amyloid β-Peptide Terminating at Amino Acid 42* , 1997, The Journal of Biological Chemistry.

[7]  John Hardy,et al.  Amyloid, the presenilins and Alzheimer's disease , 1997, Trends in Neurosciences.

[8]  K. Beyreuther,et al.  Formation of stable complexes between two Alzheimer's disease gene products: Presenilin-2 and β-amyloid precursor protein , 1997, Nature Medicine.

[9]  T. Hashimoto,et al.  Cloning and expression of cDNA for a newly identified isozyme of bovine liver 3-hydroxyacyl-CoA dehydrogenase and its import into mitochondria. , 1997, Biochimica et biophysica acta.

[10]  F. Maxfield,et al.  Microglial Cells Internalize Aggregates of the Alzheimer's Disease Amyloid β-Protein Via a Scavenger Receptor , 1996, Neuron.

[11]  J. Loike,et al.  Scavenger receptor-mediated adhesion of microglia to β-amyloid fibrils , 1996, Nature.

[12]  X. Chen,et al.  RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease , 1996, Nature.

[13]  C. Haass.  Presenile because of presenilin: the presenilin genes and early onset Alzheimer's disease , 1996, Current opinion in neurology.

[14]  R. Tanzi,et al.  REVIEWThe Gene Defects Responsible for Familial Alzheimer's Disease , 1996, Neurobiology of Disease.

[15]  B. Yankner.  Mechanisms of Neuronal Degeneration in Alzheimer's Disease , 1996, Neuron.

[16]  A. Roses,et al.  Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH , 1996, Nature Medicine.

[17]  B. Hyman,et al.  Alzheimer–associated presenilins 1 and 2 : Neuronal expression in brain and localization to intracellular membranes in mammalian cells , 1996, Nature Medicine.

[18]  S. Singer,et al.  Genetic Clues to Alzheimer's Disease , 1996, Science.

[19]  Brian J Cummings,et al.  Image analysis of β-amyloid load in Alzheimer's disease and relation to dementia severity , 1995, The Lancet.

[20]  S. Snyder,et al.  A huntingtin-associated protein enriched in brain with implications for pathology , 1995, Nature.

[21]  J. Chen,et al.  The Receptor for Advanced Glycation End Products (RAGE) Is a Cellular Binding Site for Amphoterin , 1995, The Journal of Biological Chemistry.

[22]  M. Mattson.  Free radicals and disruption of neuronal ion homeostasis in AD: A role for amyloid β-peptide? , 1995, Neurobiology of Aging.

[23]  S. Younkin.  Evidence that Aβ42 is the real culprit in alzheimer's disease , 1995 .

[24]  K. Kosik,et al.  The Alzheimer's disease sphinx: a riddle with plaques and tangles , 1994, The Journal of cell biology.

[25]  C. Behl,et al.  Hydrogen peroxide mediates amyloid β protein toxicity , 1994, Cell.

[26]  M. Mattson,et al.  A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[27]  J. Trojanowski,et al.  Paired helical filament tau in Alzheimer's disease. The kinase connection. , 1994, The American journal of pathology.

[28]  D. Selkoe,et al.  Cellular processing of β-amyloid precursor protein and the genesis of amyloid β-peptide , 1993, Cell.

[29]  M. Goedert.  Tau protein and the neurofibrillary pathology of Alzheimer's disease , 1993, Trends in Neurosciences.

[30]  Manish S. Shah,et al.  A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes , 1993, Cell.

[31]  W. Hurley,et al.  Isolation and characterization of two binding proteins for advanced glycosylation end products from bovine lung which are present on the endothelial cell surface. , 1992, The Journal of biological chemistry.

[32]  D. Kirschner,et al.  Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. , 1990, Science.

[33]  M. Ikaelsimons,et al.  Intracellular and secreted Alzheimer b-amyloid species are generated by distinct mechanisms in cultured hippocampal neurons , 1997 .

[34]  R. Tanzi,et al.  The gene defects responsible for familial Alzheimer's disease. , 1996, Neurobiology of disease.