Amyloidosis in transgenic mice expressing murine amyloidogenic apolipoprotein A-II (Apoa2c).

In mice, apolipoprotein A-II (apoA-II) self-associates to form amyloid fibrils (AApoAII) in an age-associated manner. We postulated that the two most important factors in apoA-II amyloidosis are the Apoa2(c) allele, which codes for the amyloidogenic protein APOA2C (Gln5, Ala38) and transmission of amyloid fibrils. To characterize further the contribution of the Apoa2(c) allele to amyloidogenesis and improve detection of amyloidogenic materials, we established transgenic mice that overexpress APOA2C protein under the cytomegalovirus (CMV) immediate early gene (CMV-IE) enhancer/chicken beta promoter. Compared to transgene negative (Tg(-/-)) mice that express apoA-II protein mainly in the liver, mice homozygous (Tg(+/+)) and heterozygous (Tg(+/-)) for the transgene express a high level of apoA-II protein in many tissues. They also have higher plasma concentrations of apoA-II, higher ratios of ApoA-II/apolipoprotein A-I (ApoA-I) and higher concentrations of high-density lipoprotein (HDL) cholesterol. Following injection of AApoAII fibrils into Tg(+/+) mice, amyloid deposition was observed in the testis, liver, kidney, heart, lungs, spleen, tongue, stomach and intestine but not in the brain. In Tg(+/+) mice, but not in Tg(-/-) mice, amyloid deposition was induced by injection of less than 10(-8) mug AApoAII fibrils. Furthermore, deposition in Tg(+/+) mice occurred more rapidly and to a greater extent than in Tg(-/-) mice. These studies indicate that increased levels of APOA2C protein lead to earlier and greater amyloid deposition and enhanced sensitivity to the transmission of amyloid fibrils in transgenic mice. This transgenic mouse model should prove valuable for studies of amyloidosis.

Characterization of subspecies of apolipoprotein A-I-containing lipoprotein in homozygotes for familial lecithin:cholesterol acyltransferase deficiency.

We characterized the two species of lipoproteins containing apolipoprotein A-I (apoA-I), one containing only apoA-I (LpA-I) and the other containing apoA-I and apoA-II (LpA-I/A-II), in four homozygotes for familial lecithin: cholesterol acyltransferase (LCAT) deficiency. Two homozygotes lacked both LCAT mass and activity, whereas the other two had some residual LCAT mass and activity. In these patients, the amount of all apoA-I-containing lipoproteins was one fourth that of normal control subjects, and > 60% was LpA-I. The chemical composition of both LpA-I and LpA-I/A-II is characterized by markedly decreased ratios of neutral to polar lipids compared with those of normals and the sizes of LpA-I and LpA-I/A-II particles are shifted to smaller and larger diameter ranges when compared with those of normal particles. Changes in particle diameter are also reflected in slower electrophoretic mobilities of both LpA-I and LpA-I/A-II particles. All of these abnormalities were more evident in the two homozygotes who lacked LCAT activity. Incubation of LCAT-deficient plasma with LCAT markedly corrected the chemical and physical abnormalities in both LpA-I and LpA-I/A-II particles. These data, taken together, emphasize the importance of LCAT in modifying the chemical composition, size, and shape of LpA-I and LpA-I/A-II particles.