Mouse senile amyloid deposition is suppressed by adenovirus-mediated overexpression of amyloid-resistant apolipoprotein A-II.
Apolipoprotein A-II (apoA-II), the second most abundant apolipoprotein of serum high density lipoprotein, deposits as an amyloid fibril (AApoAII) in old mice. Mouse strains with a high incidence of senile amyloidosis have the type C apoA-II gene (Apoa2(c)), whereas the strains with a low incidence of amyloidosis have the type B apoA-II gene (Apoa2(b)). In this study, to investigate whether the type B apoA-II protein inhibits the extension of amyloid fibrils, we constructed an adenovirus vector bearing the Apoa2(b) cDNA (Adex1CATApoa2(b)), which is expressed under the control of a hepatocyte-specific promoter. The mice were infected with Adex1CATApoa2(b) before induction of amyloidosis by the injection of AApoAII amyloid fibril seeds. Compared with the mice infected with the control virus, amyloid deposition was suppressed significantly in the mice infected with Adex1CATApoa2(b). Fluorometry using thioflavine T also revealed that AApoAII fibril extension was inhibited by the addition of type B apoA-II in vitro. Thus, we propose that Apoa2(b) contributes as an active inhibitor of amyloid fibril extension and overexpression of amyloid-resistant gene variant may be an attractive therapeutic target in amyloidosis.
Chiba
T
T
Field of Regeneration Control, Institute for Frontier Medical Science, Kyoto University, Kyoto, Japan.
Kogishi
K
K
Wang
J
J
Xia
C
C
Matsushita
T
T
Miyazaki
J
J
Saito
I
I
Hosokawa
M
M
Higuchi
K
K
D000256:Adenoviridae / Q000235:genetics; D000682:Amyloid / Q000378:metabolism*; D000686:Amyloidosis / Q000235:genetics / Q000628:therapy*; D000818:Animals; D016633:Apolipoprotein A-II; D001054:Apolipoproteins A / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D012333:RNA, Messenger / Q000096:biosynthesis; D013050:Spectrometry, Fluorescence; D013997:Time Factors
D000682:Amyloid; D016633:Apolipoprotein A-II; D001054:Apolipoproteins A; D012333:RNA, Messenger; C038948:apolipoprotein A-II isoproteins, human