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P1–114: Pathological effects of CLAC in the brains of APP/CLAC–P double transgenic mice
Author(s) -
Hashimoto Tadafumi,
Fujii Daisuke,
Matsuo Yuko,
Matsuura Yusuke,
Westaway David,
Iwatsubo Takeshi
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.490
Subject(s) - senile plaques , amyloid (mycology) , extracellular , genetically modified mouse , chemistry , cerebral amyloid angiopathy , hippocampus , microbiology and biotechnology , pathology , alzheimer's disease , transgene , biology , endocrinology , biochemistry , medicine , disease , gene , inorganic chemistry , dementia
Massive deposition of senile plaques (SP) in neocortices and hippocampus is the hallmark pathological lesion in Alzheimer’s disease (AD). SP are composed of amyloid fibrils formed by amyloid beta peptide (A ). We have identified CLAC (collagenous Alzheimer amyloid plaque component) in amyloid fractions of cortices from patients with AD. CLAC co-deposits with A in SP amyloid, especially in primitive-type SP in AD brains, whereas amyloid cores, vascular amyloid deposits or diffuse type plaques are CLAC-negative. We also reported that recombinant CLAC binds to fibrillized, but not soluble form of A and that recombinant CLAC inhibits the elongation phase of -amyloid fibril formation in vitro. To elucidate the pathological effects of CLAC in vivo, we generated transgenic (TG) mice overexpressing CLAC-P (CLAC precursor protein) in neurons under the control of Thy1.2 promoter. In the brains of CLAC-P TG mice, CLAC-P was expressed in neurons and extracellular deposits comprised of CLAC (i.e., extracellular fragment of CLAC-P) were observed in the neocortical neuropil. We next crossed CLAC-P TG mice with APP TG mice (i.e., J20 and TgCRND8). In the neocortices and hippocampus of the double TG mice, -amyloid plaques were strongly positive for CLAC, whereas vascular amyloid deposits. In 12-month-old double TG mice, diffuse-type plaques and huge cored plaques were markedly decreased compared to the APP TG mice, whereas compact or multi-cored plaques of medium size were predominant. The amyloid burden (i.e., percent A -positive area) in the brains of double TG mice were reduced by 30% (TgCRND8) or 50% (J20) compared to those in the littermate APP TG mice, although the levels of SDS-insoluble A quantitated by ELISA, as well as the protein expression of APP, were similar between APP TG and double TG mice. These observations suggest that the binding of CLAC to A may modify the process of -amyloid deposition.