G protein beta gamma complex-mediated apoptosis by familial Alzheimer's disease mutant of APP

Abstract

in APP 695 (Hardy, 1992). These mutations co-segregate Narasimhan Gautam 8 and with the AD phenotype (Karlinsky et al., 1992), demon- Ikuo Nishimoto 1,2,9strating that V642 mutations in APP are established causes of AD. et al., 1996). Furtherprotein APP. Expression of these mutants causes a more, it has been found that the FAD-associated V642 COS cell NK1 clone to undergo pertussis toxin-sensitive mutants of APP cause cytotoxicity in cultured cells without apoptosis in an FAD trait-linked manner by activating Aβ mediation (Yamatsuji et al., 1996a,b). Thus, the the G protein G o , which consists of Gα o and Gβγ significance, as well as the role, of Aβ deposition for AD subunits. We investigated which subunit was responsdevelopment remains unclear. ible for the induction of apoptosis by V642I APP in NK1In its structure, orientation and localization, APP is cells. In the same system, expression of mutationally similar to cell surface receptors (Kang et al., 1987; Dyrks activated Gα o or Gα i induced little apoptosis. Apoptosis et al., 1988;Weidemann et al., 1989;Schubert et al., by V642I APP was antagonized by the overexpression Ferreira et al., 1993). The cytoplasmic domain of of the carboxy-terminal amino acids 495-689 of the APP binds Fe65 protein, which has a phosphotyrosine-β-adrenergic receptor kinase-1, which blocks the binding domain related to an oncogenic signal transducer, specific functions of Gβγ. Co-transfection of Gβ2γ2Shc (Fiore et al., 1995). It also binds APP-BP1, a gene cDNAs, but not that of other Gβxγz (x ϭ 1-3; z ϭ 2, product similar to AXR1 in Arabidopsis; AXR1 is required 3), induced DNA fragmentation in a manner sensitive for normal response to the plant growth hormone auxin to bcl-2. These data implicate Gβγ as a cell death (Chow et al., 1996). These observations suggest that APP mediator for the FAD-associated mutant of APP.has not only the structure but also the function of a cell Keywords: amyloid precursor protein/apoptosis/ surface receptor. Our own earlier study (Nishimoto et al., βγ complex/familial Alzheimer's disease/G protein 1993) found that APP 695 has an intrinsic G o -stimulating domain at His657-Lys676 and forms a complex with G o through this cytoplasmic domain. It has been confirmed that the synthetic His657-Lys676 peptide activates G o

Amyloid Precursor Protein Family-induced Neuronal Death Is Mediated by Impairment of the Neuroprotective Calcium/Calmodulin Protein Kinase IV-dependent Signaling Pathway

“…Moreover, expression of familial AD mutants of APP causes apoptosis through PTX-sensitive G proteins. It was shown that these mutants induce nuclear fragmentation, which is independent of A␤ production and mediated by the G␤ 2 ␥ 2 complex of G 0 (16,20). These findings suggest that APP has an intrinsic signaling function in the cell.…”

Mitochondrial DNA Damage as a Mechanism of Cell Loss in Alzheimer's Disease

“…The accumulation of A␤-amyloid in brains with AD may be important in this regard because increased levels of Bax and p53 immunoreactivity have been localized within and around A␤-amyloid deposits in senile plaques (de la Monte et al, , 1998Su et al, 1997;Tortosa et al, 1998). Experimentally, A␤-amyloid has been shown to be neurotoxic or to induce proapoptosis and inhibit cell survival gene expression (Davis et al, 1999;Forloni et al, 1996;Giambarella et al, 1997;Gunn-Moore and Tavare, 1998;Ivins et al, 1999;Paradis et al, 1996;Prehn et al, 1996;Sayre et al, 1997a;Yamatsuji et al, 1996) and activate oxidative stress-related genes (Pappolla et al, 1998). Moreover, A␤-amyloid-induced cellular degeneration can be rescued or prevented by treatment with antioxidant or free-radical scavenger agents (Prehn et al, 1996).…”

The Gβγ-Src signaling pathway regulates TNF-induced necroptosis via control of necrosome translocation

“…A specific Gβγ complex Gβ2γ2, but not the other forms of the Gβγ complex, can mediate apoptosis induced by familial Alzheimer's disease-associated mutant of amyloid precursor protein [27]. Pertussis toxin (PTX), an exotoxin produced by bacterium Bordetella pertussis, can inhibit TNF-induced necroptosis [41,76].…”

“…However, a growing body of evidence suggests that each distinct Gβ or Gγ isoform may intrinsically possess unique biological functions [25,26]. In addition, different Gβ and Gγ combinations also seem to perform distinctive functions [27].…”