Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation

Neurobiol Dis. 1996 Feb;3(1):16-32. doi: 10.1006/nbdi.1996.0003.


Patients with trisomy 21 [Down syndrome (DS)] progressively develop amyloid beta-protein (A beta) deposits and then other features of Alzheimer's disease (AD), apparently due to increased gene dosage and thus expression of the beta-amyloid precursor protein. Because the neuropathological phenotype in older DS subjects closely resembles that of AD, the examination of DS brains of increasing age provides a unique model of the progression of AD. Here, we characterized the deposition of several A beta peptides and apolipoprotein E in formalin-fixed brain sections from 29 DS subjects between 3 and 73 years old. Amyloid plaque number and the percentage of cortical area they occupied were quantified by computerized image analysis. A beta ending at amino acid 42 (A beta 42) was the earliest form of A beta deposited in DS cortex. It was observed in 7 of 16 young (3-30 years) subjects, with the earliest deposition occurring at age 12. A beta ending at residue 40 (A beta 40) was not detected until approximately age 30, a time when degenerating neurites around A beta immunoreactive (IR) plaques were first observed, and the frequency of A beta 40 IR plaques then rose with age. Even in old (51-73 years) DS subjects, A beta 42 IR plaques were always more abundant than A beta 40 IR plaques. A beta peptides starting at aspartate 1 or pyroglutamate 3 were detected in small subsets of compacted, neuritic plaques beginning around age 30 and rose with age, the latter species always exceeding the former. Thus, the N-termini of the A beta 42 peptides abundantly deposited in very young DS subjects remain unknown. Apo E was detectable in a small subset of A beta 42 IR plaques beginning at age 12 and rose steadily with age; it clearly followed the deposition of A beta. Our analysis of very young DS brains suggests that amyloid plaque formation begins with A beta 42-ending peptides, and the number and percentage of cortical area of A beta 42 plaques increase very little with advancing age, while other heterogeneous A beta species and Apo E progressively accrue onto plaques containing A beta 42.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aging / metabolism
  • Alzheimer Disease / etiology*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / metabolism
  • Apolipoproteins E / metabolism*
  • Child
  • Child, Preschool
  • Down Syndrome / complications
  • Down Syndrome / genetics
  • Down Syndrome / metabolism*
  • Down Syndrome / pathology
  • Female
  • Humans
  • Immunoenzyme Techniques
  • Male
  • Middle Aged
  • Nerve Tissue Proteins / metabolism*
  • Neurites / pathology
  • Neurofibrillary Tangles
  • Peptide Fragments / metabolism
  • Staining and Labeling
  • Temporal Lobe / blood supply
  • Temporal Lobe / metabolism
  • Temporal Lobe / pathology


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Apolipoproteins E
  • Nerve Tissue Proteins
  • Peptide Fragments
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)