Acta Neuropathologica

, Volume 112, Issue 2, pp 163–174

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

Authors

  • Kangning Liu
    • Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease ResearchUniversity of Pennsylvania School of Medicine
  • Ingrid Solano
    • Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease ResearchUniversity of Pennsylvania School of Medicine
  • David Mann
    • Centre for Clinical Neurosciences, Greater Manchester Neuroscience Centre, Hope HospitalUniversity of Manchester
  • Cynthia Lemere
    • Center for Neurologic DiseaseHarvard Medical School
  • Marc Mercken
    • Division of Janssen Pharmaceutica N.V.Johnson & Johnson Pharmaceutical Research and Development
  • John Q. Trojanowski
    • Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease ResearchUniversity of Pennsylvania School of Medicine
    • Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease ResearchUniversity of Pennsylvania School of Medicine
Original Paper

DOI: 10.1007/s00401-006-0077-5

Cite this article as:
Liu, K., Solano, I., Mann, D. et al. Acta Neuropathol (2006) 112: 163. doi:10.1007/s00401-006-0077-5

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.

Keywords

Alzheimer’s diseaseDown’s syndromeAmyloid-beta peptideTruncationBACE

Copyright information

© Springer-Verlag 2006