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Serum
Amyloid P Component Enhances Induction of Murine Amyloidosis |
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Shinji Togashi,
Sai-Kiang Lim, Hiroo Kawano, Sadahiro Ito, Tokuhiro Ishihara, Yoshiie Okada,
Shin Nakano, Toru Kinoshita, Kyoji Horie, Vasso Episkopou, Max E. Gottesman,
Frank Costantini, Kazunori Shimada, and Shuichiro Maeda |
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The First
Department of Biochemistry (ST, SI, YO, SN, SM) and Department of Health
Sciences (TK), Yamanashi Medical University, Yamanashi; The First Department
of Pathology (HK, TI), Yamaguchi University School of Medicine, Yamaguchi;
and Research Institute for Microbial Diseases (KH, KS), Osaka University,
Osaka, Japan; Department of Genetics and Development (S-KL, FC) and Institute
of Cancer Research (MEG), Columbia University College of Physicians and
Surgeons, New York, New York; and Medical Research Council Clinical Sciences
Centre (VE), Hammersmith Hospital, London, United Kingdom |
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Serum amyloid P component
(SAP), a common component of all known types of amyloid fibrils, protects
amyloid fibrils from proteolysis in vitro. It is therefore speculated to
contribute to the deposition of amyloid fibrils in various types of amyloidoses.
However, a role for SAP in amyloid deposition is not yet known. To investigate
the relationship between SAP and amyloid deposition, we used gene targeting
techniques to generate a unique strain of mice carrying a null mutation
at the sap locus. The resultant SAP-deficient mice displayed no obvious
phenotypic abnormalities. We asked whether experimental amyloid A (AA) amyloidosis
could be induced in the SAP-deficient mice. The wild-type and SAP-deficient
mice did not differ in their synthesis of serum amyloid A, the precursor
protein of AA amyloid fibril, in response to acute inflammation. The induction
of AA amyloidosis, however, was significantly retarded in the SAP-deficient
mice relative to wild-type mice. Our experiments present, for the first
time, compelling evidence that, although not essential in the deposition
of AA amyloid, SAP significantly accelerates this reaction. Thus, SAP enhances
the induction of murine amyloidosis and may play an important role in the
pathogenesis of human amyloidoses, including Alzheimer's disease. |
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