Amyloid-beta-Induced Amyloid-beta Secretion: A Possible Feed-Forward Mechanism in Alzheimer's Disease

作者：Marsden Ian T; Minamide Laurie S; Bamburg James R^*

来源：Journal of Alzheimer's Disease, 2011, 24(4): 681-691.

DOI：10.3233/JAD-2011-101899

• A beta dimer/trimer
• cortical neurons
• hippocampal neurons
• organotypic hippocampal slice culture
• rodent A beta ELISA
• tau knockout mice

Amyloid-beta (A beta) peptides, 36-43 amino acids in length, are produced from beta- and gamma-secretase cleavage of the amyloid-beta protein precursor (A beta PP), and are one of the causative agents of Alzheimer's disease (AD). Here we show that an ELISA can detect total rodent A beta without interference from physiological concentrations of human A beta. In cultured dissociated rat cortical neurons and rat and mouse hippocampal organotypic slices, we apply the assay to measure the production of A beta in response to treatment with hydrogen peroxide, a known stimulator of A beta secretion, or human A beta dimer/trimer (A beta d/t), fractionated from the culture medium of 7PA2 cells. Peroxide increases A beta secretion by about 2 fold, similar to results from previous reports that used a different assay. Of greater significance is that physiologically relevant concentrations (similar to 250 pM) of human A beta d/t increase rodent A beta secretion from cultured rat cortical neurons by >3 fold over 4 days. Surprisingly, neither treatment with peroxide nor human A beta d/t leads to accumulation of intracellular A beta. Human A beta d/t increased >2 fold the A beta 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 A beta secretion. Together, these results support an A beta-mediated feed-forward mechanism in AD progression.

• 出版日期2011