Factors that elevate amyloid-␤ (A␤) peptide levels are associated with an increased risk for Alzheimer's disease. Insulysin has been identified as one of several proteases potentially involved in A␤ degradation based on its hydrolysis of A␤ peptides in vitro. In this study, in vivo levels of brain A␤40 and A␤42 peptides were found to be increased significantly (1.6-and 1.4-fold, respectively) in an insulysin-deficient gene-trap mouse model. A 6-fold increase in the level of the ␥-secretase-generated C-terminal fragment of the A␤ precursor protein in the insulysin-deficient mouse also was found. In mice heterozygous for the insulysin gene trap, in which insulysin activity levels were decreased Ϸ50%, brain A␤ peptides were increased to levels intermediate between those in wild-type mice and homozygous insulysin gene-trap mice that had no detectable insulysin activity. These findings indicate that there is an inverse correlation between in vivo insulysin activity levels and brain A␤ peptide levels and suggest that modulation of insulysin activity may alter the risk for Alzheimer's disease.A myloid-␤ (A␤) peptide-containing senile plaques are a prominent feature of the pathology of Alzheimer's disease (AD) and occur consistently in AD of all etiology, from earlyonset, familial-linked AD to late-onset AD of indeterminate origin (1). A␤ is formed from the amyloid precursor protein (APP) by sequential enzymatic processing. A ␤-secretase cleavage first yields the 99-aa C-terminal fragment (CTF) of APP, CTF␤, which then is cleaved by ␥-secretase to release A␤ peptides, predominately A␤40 and A␤42, and the CTF␥ peptides of 49-51 residues (2).The proteolysis of APP to yield A␤ peptides is a normal physiologic process observed in multiple cell types, although the endogenous function of APP processing and its products is still not well defined (3). To date, all of the genetic mutations linked to AD result in increased A␤ accumulation, albeit by distinct mechanisms.Although considerable effort has been directed toward generating specific inhibitors of the ␤-and ␥-secretases as a means of preventing A␤ formation (4), the mechanism of A␤ clearance also is of considerable interest because the steady-state concentrations of A␤ peptides are dependent on both their rates of synthesis and their rates of clearance. Recent studies suggest that an important route of A␤ clearance is through hydrolytic cleavage by proteases and peptidases (recently reviewed in refs. 36-38). The peptidase insulysin (EC 3.4.24.56) is one of the enzymes that has been suggested as a candidate A␤-degrading enzyme primarily based on its ability to degrade A␤ peptides in vitro (5-7).Insulysin is a zinc metalloprotease, originally identified as an insulin-degrading enzyme (8), that migrates with reported molecular masses of 110-115 kDa on SDS͞polyacrylamide gels and has no demonstrated posttranslational modifications. The observed molecular mass of insulysin is consistent with the use of the second of its two potential translation initiation sites, although N-te...

Exposure ofmurine or human lymphocytes to L-leucyl-L-leucine methyl ester (Leu-Leu-OMe) results in selective killing of cytotoxic lymphocytes, whereas helper T cells and B cells remain functionally intact. Cytolytic lymphocytes incubated in the presence of toxic concentrations of Leu-

These findings support the hypothesis that NASH associated with obesity and DM is responsible for the majority of cases of CC among Hispanics and European Americans. However, the current findings also indicate that this form of cirrhosis is unexpectedly rare among African Americans.