The molecular basis for the degeneration of neurons and the deposition of amyloid in plaques and in the cerebrovasculature in Alzheimer's disease (AD) is incompletely understood. We have proposed that one molecule common to these abnormal processes is a fragment of the Alzheimer amyloid precursor protein (APP) comprising the C-terminal 100 amino acids of this molecule (APP-C100). We tested this hypothesis by creating transgenic mice expressing APP-C100 in the brain. We report here that aging (18-28 month) APP-C100 transgenic mice exhibit profound degeneration of neurons and synapses in Ammon's horn and the dentate gyrus of the hippocampal formation. Of the 106 transgenic mice between 8 and 28 months of age that were examined, all of those older than 18 months displayed severe hippocampal degeneration. The numerous degenerating axonal profiles contained increased numbers of neurofilaments, whorls of membrane, and accumulations of debris resembling secondary lysosomes near the cell body. The dendrites of degenerating granule and pyramidal cells contained disorganized, wavy microtubules. Cerebral blood vessels had thickened refractile basal laminae, and microglia laden with debris lay adjacent to larger venous vessels. Mice transgenic for Flag-APP-C100 (in which the hydrophilic Flag tag was fused to the N terminus of APP-C100) showed a similar degree of neurodegeneration in the hippocampal formation as early as 12 months of age. The 45 control mice displayed only occasional necrotic cells and no extensive cell degeneration in the same brain regions. These findings show that APP-C100 is capable of causing some of the neuropathological features of AD.

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PRL exists within the mammotroph population in a number of different molecular forms. Several of these forms are best described as isoforms, as they have the same mol wt (24 K), but differ in their net charges. In this study we have used in vitro translation assays to ascertain the number of 24 K translation products of normal pituitary messenger RNA (mRNA), and, finding only one, have used both in vitro translation assays and subcellular fractionation to determine the intracellular site of the posttranslational modification of this single translation product. Translation of mRNA from normal pituitary tissue or GH3 cells resulted in the apparent production of a number of pre-PRLs, but in only a single rough microsome-processed form of PRL, 24 K isoform 2. Longer term translation assays utilizing a variety of isotopes failed to show any evidence for rough microsomal posttranslational modification of isoform 2. Subcellular fractionation, using a discontinuous sucrose gradient, however, produced a membrane-bound large secretory granule fraction which, when isolated, contained essentially only isoform 2, and which had the capacity to convert isoform 2 to isoforms 3 and 3' by posttranslational phosphorylation.

Erythrocytes infected with a knobby variant of Plasmodium falciparum selectively bind IgG autoantibodies in normal human serum. Quantification of membrane-bound IgG, by use of '251-labeled protein A, revealed that erythrocytes infected with the knobby variant bound 30 times more protein A than did noninfected erythrocytes; infection with a knobless variant resulted in less than a 2-fold difference compared with noninfected erythrocytes. IgG binding to knobby erythrocytes appeared to be related to parasite development, since binding of 1251-labeled protein A to cells bearing young trophozoites (less than 20 hr after parasite invasion) was similar to binding to uninfected erythrocytes. By immunoelectron microscopy, the membrane-bound IgG on erythrocytes infected with the knobby variant was found to be preferentially associated with the protuberances (knobs) of the plasma membrane. The removal of aged or senescent erythrocytes from the peripheral circulation is reported to involve the binding of specific antibodies to an antigen (senescent antigen) related to the major erythrocyte membrane protein band 3. Since affinity-purified autoantibodies against band 3 specifically bound to the plasma membrane of erythrocytes infected with the knobby variant of P. fakiparum, it is clear that the malaria parasite induces expression of senescent antigen.Erythrocytes infected with the human malaria parasite Plasmodium falciparum become immunologically altered as a result ofparasite development. These changes, which occur primarily toward the end of the parasite's 48-hr developmental cycle, have been identified by techniques capable of detecting membrane-bound immunoglobulins (1-3). It has been proposed (4) that the newly exposed antigens on the surface of infected erythrocytes are the result of parasitesynthesized proteins that are inserted into the host cell membrane; however, in spite of intense efforts by several laboratories such parasite proteins have been neither fully characterized nor specifically localized, and the manner of transport from the parasite to the erythrocyte surface is yet to be convincingly demonstrated.It is entirely possible that some of the antigenic changes observed for malaria-infected erythrocytes result from parasiteprovoked exposure or modification of host cell antigens. For example, Kay (5) showed that immunoglobulins were specifically bound to the surface of old erythrocytes, and as a result in vitro phagocytosis by macrophages occurred. These autoantibodies, found in the sera ofnormal individuals, bound to the major erythrocyte integral membrane protein, band 3 (6, 7 Elution of membrane-bound IgG was performed according to the procedure of Rekvig and Hannesta (13), except that the incubation time in isotonic glycine buffer was increased to 5 min at 0WC. Cells were layered over a 10% (wt/vol) dextran cushion and centrifuged for 2 min in a Beckman Microfuge. The pelleted cells were washed five to seven times in PBS and then incubated with antibody (70 ,ug/ml) purified by band 3-Sepharose ...