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Publication Detail
Modelling cardiac ATTR amyloidosis
  • Publication Type:
    Conference presentation
  • Publication Sub Type:
  • Authors:
    Slamova , al-shawi , mangione , ellmerich , pepys , bellotti , hawkins , Simons P
  • Name of Conference:
    XVth International Symposium on Amyloidosis
  • Conference place:
    Uppsala, Sweden
  • Conference start date:
  • Conference finish date:
INTRODUCTION Cardiac ATTR amyloidosis is an under-recognised cause of morbidity and mortality affecting the elderly. To date, no good models of cardiac ATTR amyloidosis have been reported. The rare TTRS52P variant is aggressively amyloidogenic, and is the cause of a highly penetrant adult-onset form of autosomal dominant familial amyloidosis, in which cardiac amyloidosis is a prominent feature. The recent characterization of this variant provided a new possibility for modeling cardiac ATTR amyloidosis. MATERIALS & METHODS Transgenic mice were generated on the C57BL/6 background by pronuclear microinjection. hTTRS52P transgenic mice were bred with wild-type mice, or crossed with TTR knockouts. Human TTR was assayed by electroimmunoassay using anti-hTTR antibody (Dako). Western blots of serum proteins were probed with anti-TTR antisera (Dako or Binding Site). Amyloid deposition was assessed by Congo red staining and polarizing microscopy. Amyloid fibril type was assessed by immunoperoxidase staining using anti-TTR (Dako) anti-SAA (R&D systems) and anti-apoAII (a kind gift of Prof. Higuchi). RESULTS The concentrations of hTTR were assayed in sera of hemizygous hTTRS52P transgenic mice, and measured to be 1.6 ± 0.14 mg/mL (mean ± SD) in males, and 1.1 ± 0.18 mg/mL in females. By Western blot analysis of transgenic mouse serum alongside normal human serum, an additional slower migrating minor band was consistently observed in transgenic mouse serum, which was abolished by PNGase F treatment. Congo red staining revealed no amyloid in 22 different tissues in untreated transgenic mice of ages up to 22 months. In contrast, amyloid deposits were found in mice injected 4-7 months previously with splenic amyloid from a hTTRS52P patient. Among 29 mice analysed, amyloid was detected in 22, including 17 with cardiac amyloid. In each case, there was positive immune histochemical staining for human TTR in the amyloid deposits (Fig. 1), and no staining for apoAII or SAA. No difference was apparent in amyloid deposition between mice wild-type, heterozygous or knockout for the endogenous TTR. Notably, cardiac amyloid was present in 16 of 17 amyloid-seeded transgenic males, but only 1 of 12 females. DISCUSSION The transgenic mice reported here express hTTRS52P variant at concentrations comparable to those in humans. Higher concentrations were measured in males than in females, as is the case in people. The minor glycosylated component is consistent with misfolding of nascent protein in the secretory pathway, and tagging for ER-associated decay. Despite this, and the early onset of amyloidosis in hTTRS52P patients, no amyloid deposition was detected in untreated transgenic mice. In contrast, amyloid was consistently observed in mice of similar or younger ages that had been seeded with patient-derived amyloid. This suggests that endogenous formation of hTTRS52P amyloid seeds is limiting in mice. A further striking observation was the much greater incidence of amyloid in transgenic males than in females, which might reflect the large male preponderance of clinical cardiac ATTR amyloidosis. Although the amounts of amyloid in these mice were modest, these mice promise to be invaluable for investigating the pathogenesis of cardiac ATTR amyloidosis as well as for evaluating therapies and diagnostic methods.
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