title: Amyloid-β-induced amyloid-β secretion: a possible feed-forward mechanism in Alzheimer's Disease.
abstract: Amyloid-β (Aβ) peptides, 36-43 amino acids in length, are produced from β- and γ-secretase cleavage of the amyloid-β protein precursor (AβPP), and are one of the causative agents of Alzheimer's disease (AD). Here we show that an ELISA can detect total rodent Aβ without interference from physiological concentrations of human Aβ. In cultured dissociated rat cortical neurons and rat and mouse hippocampal organotypic slices, we apply the assay to measure the production of Aβ in response to treatment with hydrogen peroxide, a known stimulator of Aβ secretion, or human Aβ dimer/trimer (Aβd/t), fractionated from the culture medium of 7PA2 cells. Peroxide increases Aβ secretion by about 2 fold, similar to results from previous reports that used a different assay. Of greater significance is that physiologically relevant concentrations (~250 pM) of human Aβd/t increase rodent Aβ secretion from cultured rat cortical neurons by >3 fold over 4 days. Surprisingly, neither treatment with peroxide nor human Aβd/t leads to accumulation of intracellular Aβ. Human Aβd/t increased >2 fold the Aβ secreted by organotypic hippocampal slices from tau knock-out mice whether or not they expressed a human tau transgene, suggesting tau plays no role in enhanced Aβ secretion. Together, these results support an Aβ-mediated feed-forward mechanism in AD progression.
authors.affiliation: Department of Biochemistry and Molecular Biology and Molecular, Cellular and Integrative Neuroscience Program, Colorado State University, Fort Collins, CO, USA.
authors.forename: Ian T
authors.initials: IT
authors.lastname: Marsden
authors.forename: Laurie S
authors.initials: LS
authors.lastname: Minamide
authors.forename: James R
authors.initials: JR
authors.lastname: Bamburg
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D016466:CHO Cells; D002417:Cattle; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)