BackgroundAggregatable amyloid β-peptide (Aβ) and non-aggregatable p3-Alcα are metabolic products of the γ-secretase cleavage of amyloid β-protein precursor (APP) and Alcadeinα (Alcα), respectively. Familial AD (FAD) -linked mutations in the presenilin 1 or 2 (PS1 or PS2) component of γ-secretase can cause alternative intramembranous processing of APP and Alcα, leading to a coordinated generation of variants of both Aβ and p3-Alcα. Variant Alcα peptides have been observed in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment and sporadic Alzheimer's disease (AD). Since, like APP, Alcα is largely expressed in brain, one might predict that alternative processing of Alcα would be reflected in body fluids of some AD patients. These patients with misprocessing of multiple γ-secretase substrates might define an endophenotype of p3-Alcα, in whom AD is due either to dysfunction of γ-secretase or to a disorder of the clearance of hydrophobic peptides such as those derived from transmembrane domains.ResultsWe developed a simple procedure for extraction of p3-Alcα from plasma and for analyzing this extract in a sensitive, p3-Alcα-specific sandwich enzyme-linked immunosorbent assay (ELISA) system. Plasma p3-Alcα levels and Aβ40 levels were examined in sporadic AD subjects from two independent Japanese cohorts. In some of these patients, levels of plasma p3-Alcα were significantly higher, and were accompanied by parallel changes in Aβ40 levels. This AD-related difference was more marked in female subjects, but this phenomenon was not observed in subjects with frontotemporal lobar degeneration (FTLD).ConclusionReagents and procedures have been established that enable extraction of p3-Alcα from plasma and for quantification of plasma p3-Alcα levels by ELISA. Some populations of AD subjects apparently show increased levels of both p3-Alcα and Aβ40. Quantification of p3-Alcα level may be useful as a readily accessible biomarker for a population of sporadic AD patients in which disease pathogenesis is associated with either dysfunction of γ-secretase or with a disorder of the clearance of transmembrane domain-derived peptides.

Mesothelioma is a type of malignant tumor that most commonly arises from the pleural or peritoneal membrane and is usually associated with previous exposure to asbestos. In humans, ERC/ mesothelin is expressed on the normal mesothelium and in some cancers such as mesothelioma or ovarian carcinoma. Recently, several enzyme-linked immunosorbent assay (ELISA) systems for ERC/mesothelin have been developed, the reported usefulness of which has been assessed and demonstrated as a diagnostic tool. However, the basic roles or physiological functions of, and relationship between, ERC/mesothelin and asbestos exposuremediated carcinogenesis remain to be resolved. In order to elucidate the precise mechanism, animal models of mesothelioma are desperately needed. In this study, we consider the development of a novel specific ELISA system for not only rat N-ERC/mesothelin but also C-ERC/mesothelin, and the first data on the presence of rat ERC/ mesothelin in the body fluids of rat malignant mesotheliomabearing nude mice. The transplanted mice have revealed the higher concentrations of rat N-ERC/mesothelin in the blood and ascites than C-ERC/mesothelin. We hope these novel ELISA systems are useful in the rat model system to clarify the mechanism of asbestosinduced carcinogenesis and to develop new effective drugs for mesothelioma. (Cancer Sci 2008; 99: 666-670) T he number of cases of mesothelioma caused by exposure to asbestos is growing, and as exemplified by the shocking events in 2005 and highlighted in TV and newspaper reports every day in Japan, this condition represents an enormous social problem.Mesothelioma is a type of malignant tumor that most commonly arises from the pleural or peritoneal membrane. It is believed that mesothelioma is caused by the inhalation of asbestos fibers. However, how the aspirated asbestos in the lung might provoke tumor formation in the pleural membrane that covers the lungs, or the peritoneal membrane, has not yet been clarified. (1,2) In regard to human mesothelioma, a group from Australia has reported that soluble mesothelin-related protein (SMRP), the Cterminal fragment of mesothelin, may be a tumor marker. Another group from National Institute of Health has reported that the N-terminal fragment of mesothelin may be a mesothelioma marker.(3-11) Also, Shiomi et al. reported the usefulness of the N-ERC/mesothelin as a serum marker for mesothelioma. The mesothelin protein is present in the normal mesothelium, a membrane lining several body cavities including the pleura, peritoneum, and pericardium. It could be speculated that mesothelioma derived from the mesothelium should demonstrate overexpression of mesothelin. This protein, 622 amino acids in length, is expressed as a GPI anchor-type membranous protein of with a molecular weight of about 71 kDa, that is cleaved by a furin-like protease into the 31 kDa N-terminal fragment and 40 kDa C-terminal fragment.On the other hand, we have conducted research on the Eker model rat, a rat model of renal cell calcinoma, and cloned the Erc gene, whic...

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