title: The evolution of A beta peptide burden in the APP23 transgenic mice: implications for A beta deposition in Alzheimer disease.
abstract: BACKGROUND
  High levels of A beta in the cerebral cortex distinguish demented Alzheimer's disease (AD) from nondemented elderly individuals, suggesting that decreased amyloid-beta (A beta) peptide clearance from the brain is a key precipitating factor in AD.
  
  
  METHODS
  The levels of A beta in brain and plasma as well as apolipoprotein E (ApoE) in brain were investigated by enzyme-linked immunosorbent assay (ELISA) and Western blotting at various times during the life span of the APP23 transgenic (Tg) and control mice. Histochemistry and immunocytochemistry were used to assess the morphologic characteristics of the brain parenchymal and cerebrovascular amyloid deposits and the intracellular amyloid precursor protein (APP) deposits in the APP23 Tg mice.
  
  
  RESULTS
  No significant differences were found in the plasma levels of A beta between the APP23 Tg and control mice from 2-20 months of age. In contrast, soluble A beta levels in the brain were continually elevated, increasing 4-fold at 2 months and 33-fold in the APP23 Tg mice at 20 months of age when compared to the control mice. Soluble A beta42 was about 60% higher than A beta40. In the APP23 Tg mice, insoluble A beta40 remained at basal levels in the brain until 9 months and then rose to 680 microg/g cortex by 20 months. Insoluble A beta40 was negligible in non-Tg mice at all ages. Insoluble A beta42 in APP23 Tg mice rose to 60 microg/g cortex at 20 months, representing 24 times the control A beta42 levels. Elevated levels of ApoE in the brain were observed in the APP23 Tg mice at 2 months of age, becoming substantially higher by 20 months. ApoE colocalized with A beta in the plaques. Beta-amyloid precursor protein (betaAPP) deposits were detected within the neuronal cytoplasm from 4 months of age onward. Amyloid angiopathy in the APP23 Tg mice increased markedly with age, being by far more severe than in the Tg2576 mice.
  
  
  CONCLUSIONS
  We suggest that the APP23 Tg mouse may develop an earlier blockage in A beta clearance than the Tg2576 mice, resulting in a more severe accumulation of A beta in the perivascular drainage pathways and in the brain. Both Tg mice reflect decreased A beta elimination and as models for the amyloid cascade they are useful to study AD pathophysiology and therapy.
authors.affiliation: The Longtine Center for Molecular Biology and Genetics, Sun Health Research Institute, Sun City, Arizona 85351, USA.
authors.forename: Y M
authors.initials: YM
authors.lastname: Kuo
authors.forename: T G
authors.initials: TG
authors.lastname: Beach
authors.forename: L I
authors.initials: LI
authors.lastname: Sue
authors.forename: S
authors.initials: S
authors.lastname: Scott
authors.forename: K J
authors.initials: KJ
authors.lastname: Layne
authors.forename: T A
authors.initials: TA
authors.lastname: Kokjohn
authors.forename: W M
authors.initials: WM
authors.lastname: Kalback
authors.forename: D C
authors.initials: DC
authors.lastname: Luehrs
authors.forename: T A
authors.initials: TA
authors.lastname: Vishnivetskaya
authors.forename: D
authors.initials: D
authors.lastname: Abramowski
authors.forename: C
authors.initials: C
authors.lastname: Sturchler-Pierrat
authors.forename: M
authors.initials: M
authors.lastname: Staufenbiel
authors.forename: R O
authors.initials: RO
authors.lastname: Weller
authors.forename: A E
authors.initials: AE
authors.lastname: Roher
mesh_terms: D000375:Aging / Q000502:physiology; D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000097:blood / Q000378:metabolism*; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)