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Analyses of the biologic effects of mutations in the BRI2 (ITM2b) and the amyloid β precursor protein (APP) genes support the hypothesis that cerebral accumulation of amyloidogenic peptides in familial British and familial Danish dementias and Alzheimer’s disease (AD) is associated with neurodegeneration. We have used somatic brain transgenic technology to express the BRI2 and BRI2-Aβ1-40 transgenes in amyloid β protein precursor (APP) mouse models. Expression of BRI2-Aβ1-40 mimics the suppressive effect previously observed using conventional transgenic methods, further validating the somatic brain transgenic methodology. Unexpectedly, we also find that expression of wild type human BRI2 reduces cerebral Aβ deposition in an AD mouse model. Additional data indicate that the 23 amino acid peptide, Bri23, released from BRI2 by normal processing is present in human cerebrospinal fluid (CSF), inhibits Aβ aggregation in vitro, and mediates its anti-amyloidogenic effect in vivo. These studies demonstrate that BRI2 is a novel mediator of Aβ deposition in vivo.

We have previously reported that treatment of isolated rat heart mitochondria with the free radical-generating system Cu 2+ / tert -butylhydroperoxide produces striking changes in the adenine nucleotide translocase (ANT) of the inner membrane. These changes include a small increase in apparent molecular weight as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, followed by its disappearance from the polypeptide profile upon further oxidant treatment (Zwizinski and Schmid (1992) Arch. Biochem. Biophys. 294, 178-183). In order to characterize its peroxidative modification in more detail, we have purified rat heart ANT and prepared polyclonal antibody against it. Using this antibody, we have observed that increasing oxidant treatment results in a gradual increase in the ANT protein′s apparent molecular weight by up to 1 kDa. The progressive nature of the molecular weight shift, which parallels the generation of thiobarbituric acid reactive substances, supports the hypothesis that this phenomenon may be the result of covalent addition of increasing amounts of lipid peroxidation products. Strong oxidative treatment of cardiac mitochondria also causes fragmentation and polymerization of the ANT protein. However, Western blot analysis showed that a major portion of the original ANT survives even extensive oxidation as a distinct, modified protein. Therefore, the almost complete disappearance of ANT from Coomassie-stained gels appears to be the result of cross-linking and fragmentation reactions, as well as a decreased efficiency of the Coomassie staining. Because a measurable molecular weight shift of ANT occurs at the mildest oxidative treatment tested (resulting in the production of only 1.1 nmol malondialdehyde/mg protein), it may be relevant as a parameter of myocardial ischemia-reperfusion injury.

Numerous studies have established a pivotal role for Abeta42 in Alzheimer's disease (AD) pathogenesis. In contrast, although Abeta40 is the predominant form of amyloid beta (Abeta) produced and accumulates to a variable degree in the human AD brain, its role in AD pathogenesis has not been established. It has generally been assumed that an increase in Abeta40 would accelerate amyloid plaque formation in vivo. We have crossed BRI-Abeta40 mice that selectively express high levels of Abeta40 with both Tg2576 (APPswe, K670N+M671L) mice and BRI-Abeta42A mice expressing Abeta42 selectively and analyzed parenchymal and cerebrovascular Abeta deposition in the bitransgenic mice compared with their singly transgenic littermates. In the bitransgenic mice, the increased steady-state levels of Abeta40 decreased Abeta deposition by 60-90%. These results demonstrate that Abeta42 and Abeta40 have opposing effects on amyloid deposition: Abeta42 promotes amyloid deposition but Abeta40 inhibits it. In addition, increasing Abeta40 levels protected BRI-Abeta40/Tg2576 mice from the premature-death phenotype observed in Tg2576 mice. The protective properties of Abeta40 with respect to amyloid deposition suggest that strategies that preferentially target Abeta40 may actually worsen the disease course and that selective increases in Abeta40 levels may actually reduce the risk for development of AD.

Background The mammalian Vps10p sorting receptor family is a group of 5 type I membrane homologs (Sortilin, SorLA, and SorCS1-3). These receptors bind various cargo proteins via their luminal Vps10p domains and have been shown to mediate a variety of intracellular sorting and trafficking functions. These proteins are highly expressed in the brain. SorLA has been shown to be down regulated in Alzheimer's disease brains, interact with ApoE, and modulate Aβ production. Sortilin has been shown to be part of proNGF mediated death signaling that results from a complex of Sortilin, p75NTR and proNGF. We have investigated and provide evidence for γ-secretase cleavage of this family of proteins. Results We provide evidence that these receptors are substrates for presenilin dependent γ-secretase cleavage. γ-Secretase cleavage of these sorting receptors is inhibited by γ-secretase inhibitors and does not occur in PS1/PS2 knockout cells. Like most γ-secretase substrates, we find that ectodomain shedding precedes γ-secretase cleavage. The ectodomain cleavage is inhibited by a metalloprotease inhibitor and activated by PMA suggesting that it is mediated by an α-secretase like cleavage. Conclusion These data indicate that the α- and γ-secretase cleavages of the mammalian Vps10p sorting receptors occur in a fashion analogous to other known γ-secretase substrates, and could possibly regulate the biological functions of these proteins.