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Published December 2005 | Published + Supplemental Material
Journal Article Open

Persistent amyloidosis following suppression of Aβ production in a transgenic model of Alzheimer disease

Abstract

Background: The proteases (secretases) that cleave amyloid-β (Aβ) peptide from the amyloid precursor protein (APP) have been the focus of considerable investigation in the development of treatments for Alzheimer disease. The prediction has been that reducing Aβ production in the brain, even after the onset of clinical symptoms and the development of associated pathology, will facilitate the repair of damaged tissue and removal of amyloid lesions. However, no long-term studies using animal models of amyloid pathology have yet been performed to test this hypothesis. Methods and Findings: We have generated a transgenic mouse model that genetically mimics the arrest of Aβ production expected from treatment with secretase inhibitors. These mice overexpress mutant APP from a vector that can be regulated by doxycycline. Under normal conditions, high-level expression of APP quickly induces fulminant amyloid pathology. We show that doxycycline administration inhibits transgenic APP expression by greater than 95% and reduces Aβ production to levels found in nontransgenic mice. Suppression of transgenic Aβ synthesis in this model abruptly halts the progression of amyloid pathology. However, formation and disaggregation of amyloid deposits appear to be in disequilibrium as the plaques require far longer to disperse than to assemble. Mice in which APP synthesis was suppressed for as long as 6 mo after the formation of Aβ deposits retain a considerable amyloid load, with little sign of active clearance. Conclusion: This study demonstrates that amyloid lesions in transgenic mice are highly stable structures in vivo that are slow to disaggregate. Our findings suggest that arresting Aβ production in patients with Alzheimer disease should halt the progression of pathology, but that early treatment may be imperative, as it appears that amyloid deposits, once formed, will require additional intervention to clear.

Additional Information

© 2005 Jankowsky et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: June 14, 2005; Accepted: August 22, 2005; Published: November 15, 2005. Academic Editor: Adriano Aguzzi, Zürich University, Switzerland We thank Patrick Tremblay for helpful advice on the tet system at a critical time in the project, and Mark Mayford for sharing the CaMKIIα-tTA mice through Jackson Laboratory. We also thank Fraser Moss for saving several immunoblots with last-minute shipments, Andy Groves for many thoughtful discussions, Neil Segil for generously sharing his laboratory and equipment, Beth Olson, Natasha Bouey, and Yolanda Jackson for outstanding animal care, Debbie Swing for expert microinjection, and Dave Fromholt for genotyping and dissection. We gratefully acknowledge Takeda Chemical Industries for providing antibodies BAN50, BA27, and BC05, Konrad Beyreuther and Andreas Weidemann for providing 22C11 antibody, and Ed Koo for sharing CT15 antibody. This work was supported by grants from the Johns Hopkins Alzheimer's Disease Research Center (JLJ), the National Alliance for Research on Schizophrenia and Depression (Young Investigator Award [JLJ]), the Rose Hills Foundation (JLJ), the Alzheimer's Association (Zenith Award [DRB]), the National Institute of Aging (K01 AG26144–01 [JLJ], P50 AGO5146–20 [DRB], R01 AG006656–16 [SGY], and P01 AG015453 [SGY]), the National Institute of Neurologic Disease and Stoke (R01 NS 047225 [DRB]), and the National Cancer Institute (NAJ and NGC). The funding agencies generously provided for research supplies, animal care, and salary support; the funders of this work had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Author Contributions: JLJ and DRB designed the study and wrote the manuscript, JLJ, HHS, VG, JCW, LHY, SGY and DRB performed experiments, NAJ and NGC generated transgenic founders, HAL assisted with data interpretation, and AVS performed statistical analyses.

Attached Files

Published - JANplosmed05.pdf

Supplemental Material - journal.pmed.0020355.sg001.TIF

Supplemental Material - journal.pmed.0020355.sg002.PSD

Supplemental Material - journal.pmed.0020355.sg003.PSD

Supplemental Material - journal.pmed.0020355.sg004.JPG

Supplemental Material - journal.pmed.0020355.sg005.TIF

Supplemental Material - journal.pmed.0020355.sg006.PSD

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August 22, 2023
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