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Abstract: Beta amyloid peptide is generated from amyloid precursor protein (APP) by proteolytic cleavage of β- and γ-secretases, and plays a critical role in the pathogenesis of Alzheimer’s disease. Since γ-secretase cleaves several proteins including APP and Notch in a number of cell types, it is important to understand the conditions determining γ-secretase substrate specificity. In the present study, inhibition of Rac1 attenuated γ-secretase activity for APP, resulting in decreased production of the APP intracellular domain but accumulated C-terminal fragments (APP-CTF). In contrast, Rac1 inhibitor, NSC23766 increased production of the Notch1 intracellular domain but slightly decreased the ectodomain-shed form of Notch1 (NotchΔE). To elucidate the mechanism underlying these observations, we performed co-immunoprecipitation experiments to analyze the interaction between Rac1 and presenilin1 (PS1), a component of the γ-secretase complex. Inhibition of Rac1 enhanced its interaction with PS1. Under the same condition, PS1 interacted more strongly with NotchΔE than with APP-CTF. Our results suggested that PS1 determines the preferred substrate for γ-secretase between APP and Notch1, depending on the activation status of Rac1. [Copyright &y& Elsevier]

Abstract: Both active and passive immunization to eliminate amyloid plaques from the brain of patients with Alzheimer’s disease (AD) have confirmed that amyloid beta (Aβ) vaccination does not only result in clearance of Aβ plaques but improves behavioral-cognitive deficits in animal models of AD. In the present study, the levels of naturally occurring serum antibodies against Aβ were measured in Tg2576 mice at various ages using ELISA to determine the relationship between aging and the level of anti-Aβ autoantibody. The level of anti-Aβ antibody fell significantly at the age of 9 months, at the age when amyloid plaques started to appear in the brain of Tg2576 mice, and was persistently low thereafter. However, serum immunoglobulin (Ig) level was elevated in older transgenic mice compared with younger transgenic mice suggesting that the reduced level of anti-Aβ autoantibody was not merely due to deterioration of the immune response in aged Tg2576 mice. [Copyright &y& Elsevier]

Abstract: Constitutive and PKC-regulated α-secretase pathways have been reported to produce the secreted form of α-secretase-derived APP (sAPPα). Here, we examined putative role of furin in the regulation of α-secretase activity in vitro and in vivo. Overexpression of the prodomain of furin and infection with a furin-specific inhibitor significantly reduced the levels of sAPPα regardless of PKC activity, whereas total APP levels remained unchanged. Furin mRNA levels in the brains of AD patients and Tg2576 mice were significantly lower than those in controls, whereas ADAM10 and TACE mRNA levels were much alike between Tg2576 and littermate mice. Moreover, the injection of furin-adenovirus into Tg2576 mouse brains markedly increased α-secretase activity and reduced β-amyloid protein (Aβ) production in infected brain regions. Our results suggest that furin enhances α-secretase activity via the cleavage of ADAM10 and TACE, and that attenuated furin activity is connected to the production of Aβ. [Copyright &y& Elsevier]