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

  • Kangning Liu
  • Ingrid Solano
  • David Mann
  • Cynthia Lemere
  • Marc Mercken
  • John Q. Trojanowski
  • Virginia M.-Y. Lee
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

Authors and Affiliations

  • Kangning Liu
    • 1
  • Ingrid Solano
    • 1
  • David Mann
    • 2
  • Cynthia Lemere
    • 3
  • Marc Mercken
    • 4
  • John Q. Trojanowski
    • 1
  • Virginia M.-Y. Lee
    • 1
  1. 1.Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease ResearchUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  2. 2.Centre for Clinical Neurosciences, Greater Manchester Neuroscience Centre, Hope HospitalUniversity of ManchesterSalfordUK
  3. 3.Center for Neurologic DiseaseHarvard Medical SchoolBostonUSA
  4. 4.Division of Janssen Pharmaceutica N.V.Johnson & Johnson Pharmaceutical Research and DevelopmentBeerseBelgium