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Characterization of Aβ11-40/42 peptide deposition in Alzheimer’s disease and young Down’s syndrome brains: implication of N-terminally truncated Aβ species in the pathogenesis of Alzheimer’s disease

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Abstract

Senile plaques (SPs), one of two defining lesions of Alzheimer’s disease (AD), are composed of a mixture of full-length Aβ1-40/42, and N- or C-terminally truncated Aβ peptides, including Aβ11-40/42. Sequential proteolysis of amyloid precursor protein (APP) by β- and γ-secretases produces Aβ1-40/42, but β-site APP-cleaving enzyme 1 (BACE1), the major β-secretase, also generates Aβ11-40/42, and BACE1 overexpression in cultured cells results primarily in secretion of Aβ11-40/42. The ratio of Aβ11-40/42 to Aβ1-40/42 depends on the ratio of BACE1 to APP, and Aβ11-40/42 can be generated from both full-length APP and its carboxy-terminal fragment (C99). Here, we investigated the role of Aβ11-40/42 in the pathogenesis of AD and Down’s syndrome (DS) brains. We demonstrated significant amount of Aβ11-42 in DS brains by Western blots. While pyroAβ11-42-modified Aβ species existed predominantly in mature SP cores in AD brain sections, both unmodified free Aβ11-40 and pyro-modified Aβ11-40 are detected in vascular amyloid deposits by immunohistochemistry. Using novel ELISAs for quantifying free Aβ11-40/42 and pyroAβ11-40/42, we showed that insoluble Aβ11-42 predominated in extracts of AD and DS brains. This is the first systematic study of Aβ11-40/42 in neurodegenerative Aβ amyloidosis implicating Aβ11-40/42 in SP formation of AD and DS brains. The detection of Aβ11-42 in young DS brain suggests an early role for this N-terminally truncated Aβ peptide in the pathogenesis of SPs in AD and DS.

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Acknowledgments

We gratefully thank Janssens Pharmaceutica for providing antibodies M11, JRFAbN and JRFAb42. We also thank Takeda Pharmaceuticals for antibody BA27, and Eli Lilly and Company for antibody M266. We thank Dr D. Teplow for providing the Aβ11-40/42 peptides. We thank Drs V. Zhukareva and M. Forman for help with brain sample selection and Ms T. Schuck for help with tissue processing. We thank the following individuals from tissue banks for sending brain from their tissue collection: Ms Virginia Buckles (Washington University), Mr Robert Johnson (University of Maryland) and Ms Inna Logvinsky (University of Miami). We also thank Drs R. DeMattos and D. Holtzman for the acid urea gel protocol, and E. Greenbaum and C. Jordan for technical assistance. We appreciate Drs V. Zhukareva, L. Jia and E. B Lee for critical reading of the manuscript. This work was supported by grants from the National Institute on Aging (AG-10124, AG-14449 and AG-11542).

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA

    Kangning Liu, Ingrid Solano, John Q. Trojanowski & Virginia M.-Y. Lee

  2. Centre for Clinical Neurosciences, Greater Manchester Neuroscience Centre, Hope Hospital, University of Manchester, Salford, M6 8HD, UK

    David Mann

  3. Center for Neurologic Disease, Harvard Medical School, Boston, MA, 02115, USA

    Cynthia Lemere

  4. Division of Janssen Pharmaceutica N.V., Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, 2340, Beerse, Belgium

    Marc Mercken

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  1. Kangning Liu
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Correspondence to Virginia M.-Y. Lee.

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Liu, K., Solano, I., Mann, D. et al. Characterization of Aβ11-40/42 peptide deposition in Alzheimer’s disease and young Down’s syndrome brains: implication of N-terminally truncated Aβ species in the pathogenesis of Alzheimer’s disease. Acta Neuropathol 112, 163–174 (2006). https://doi.org/10.1007/s00401-006-0077-5

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