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Early formation of mature amyloid‐β protein deposits in a mutant APP transgenic model depends on levels of Aβ 1–42
Author(s) -
Rockenstein Edward,
Mallory Margaret,
Mante Michael,
Sisk Abyanné,
Masliaha Eliezer
Publication year - 2001
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.1247
Subject(s) - synaptophysin , genetically modified mouse , neurofilament , neocortex , olfactory bulb , hippocampus , hippocampal formation , amyloid precursor protein , biology , amyloid (mycology) , neurite , cortex (anatomy) , microbiology and biotechnology , transgene , pathology , immunohistochemistry , endocrinology , neuroscience , alzheimer's disease , gene , biochemistry , medicine , central nervous system , immunology , disease , in vitro
The main objective of the present study was to develop an alternative singly‐transgenic (tg) hAPP model where amyloid deposition will occur at an earlier age. For this purpose, we generated lines of tg mice expressing hAPP751 cDNA containing the London (V717I) and Swedish (K670M/N671L) mutations under the regulatory control of the murine (m)Thy‐1 gene (mThy1‐hAPP751). In the brains of the highest (line 41) and intermediate (lines 16 and 11) expressers, high levels of hAPP expression were found in neurons in layers 4–5 of the neocortex, hippocampal CA1 and olfactory bulb. As early as 3–4 months of age, line 41 mice developed mature plaques in the frontal cortex, whereas at 5–7 months plaque formation extended to the hippocampus, thalamus and olfactory region. Ultrastructural and double‐immunolabeling analysis confirmed that most plaques were mature and contained dystrophic neurites immunoreactive with antibodies against APP, synaptophysin, neurofilament and tau. In addition, a decrease in the number of synaptophysin‐immunoreactive terminals was most prominent in the frontal cortex of mice from line 41. Mice from line 11 developed diffuse amyloid deposits at 11 months of age, whereas mice from line 16 did not show evidence of amyloid deposition. Analysis of Aβ by ELISA showed that levels of Aβ 1–40 were higher in mice that did not show any amyloid deposits (line 16), whereas Aβ 1–42 was the predominant species in tg animals from the lines showing plaque formation (lines 41 and 11). Taken together this study indicates that early onset plaque formation depends on levels of Aβ 1–42 . J. Neurosci. Res. 66:573–582, 2001. © 2001 Wiley‐Liss, Inc.