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Non-hereditary apolipoprotein AI-associated pulmonary amyloid

Apolipoprotein AI amyloidosis (Apo AI) characteristically is associated with the deposition in tissue of fibrils composed of mutated Apo AI; however, amyloid deposits comprised of the native molecules have been noted in the aorta of elderly humans. We now report that an amyloid-containing nodule in the lung of a 76-year-old asymptomatic female was composed of Apo AI that, on the basis of genomic DNA analysis, was formed from wild-type protein. This finding provides further evidence that the aging process is associated with the propensity of normally soluble unmutated serum proteins to deposit pathologically as amyloid. Introduction: Typically, the apolipoprotein (Apo) AI-associated amyloidoses are autosomal, dominant, familial disorders characterized by the pathologic deposition as fibrils of N-terminal fragments of mutated Apo AI molecules in the nerves, kidney, liver, heart, or other organs [1]. Notably, however, inheritable variations in Apo AI sequence may not necessarily render these components amyloidogenic, as demonstrated by the discovery that the Apo AIrelated deposits seen in the aortic intima of older humans (as well as the pulmonary vasculature of aged dogs) is comprised of wild-type protein [2,3]. We now report our analysis of amyloid contained in a 1.6 cm lung nodule (Figure 1) from an otherwise healthy, non-smoking, 76-year-old Caucasian female, which represented an amyloidoma composed of unmutated Apo AI. Methods: Amyloid extracted from sections cut from a formalin-fixed, paraffin-embedded CT-guided needle biopsy specimen was reduced, alkylated, digested with trypsin, and subjected to tandem mass spectrometry (MS/MS) [4,5]. For molecular analysis, genomic DNA was prepared from peripheral blood leukocytes and the 700 base pairs comprising exon 4 of the Apo AI gene were amplified by PCR using primers and conditions, as already published [6]; the products were sequenced at the University of Tennessee’s Molecular Biology Facility. The procedures for immunohistochemistry, using as primary reagent a murine anti-human Apo AI mAb, were as previously described [7]. Results and discussion: Analyses by MS/MS of the peptides resulting from trypsin digestion of the reduced and alkylated amyloid extracted from the biopsy specimen revealed components that spanned residues 24–40 and 62–77 of normal Apo AI; further, no mutations were found in Apo AI-encoding exons of the patient’s genomic DNA. The Apo AI nature of the amyloid was confirmed immunohistochemically (Figure 1). Our data provide evidence for yet another manifestation of Apo AI-related disease in an elderly individual in whom the pulmonary amyloid deposit consisted of wild-type protein. Acknowledgements: Authors thank Sallie Macy and Craig Wooliver for the studies illustrated in Figure 1. Declaration of interest: Research was supported, in part, by United States Public Health Service Figure 1. (a,b) CT scan of the lung showing the presence of the amyloidoma. (a) Bone window with increased contrast; (b) Soft tissue window. (c,d) Congo red and immunohistochemical analysis of the same section of the patient’s lung. (c) Congo red stain; (d) Immunostaining of the amyloid by an anti-Apo AI antibody (ABC method). Original magnifications, 6200. 219