Aβ42 generation is toxic to endothelial cells and inhibits eNOS function through an Akt/GSK-3β signaling-dependent mechanism

Intraneuronal β-Amyloid Expression Downregulates the Akt Survival Pathway and Blunts the Stress Response

“…1, 2). The mechanisms linking the effects of A␤42 to disruption of Akt signaling are not completely clear; however, we have shown previously that A␤42 may disrupt the interaction between Akt and its activator, PDK-1 (phosphoinositide-dependent kinase-1) (Suhara et al, 2003). Although we observe that A␤42 interferes with the Akt survival pathway, there is evidence that the MAPK pathway involving ERK2 may also be affected in an in vivo model for intracellular A␤ accumulation (Echeverria et al, 2004).…”

“…Several reports using transgenic animals (LaFerla et al, 1995;Link, 1995;Iijima et al, 2004) or cultured cells (Johnstone et al, 1996;Querfurth et al, 2001;Zhang et al, 2002;Suhara et al, 2003) have provided direct observations on the effects of intracellular A␤42 expression or injection. However, our inducible adenoviral vector system (Magrane et al, 2004) has allowed us to test molecular mechanisms of intracellular A␤42 toxicity following controlled expression within cultured neurons and other primary cell types.…”

“…1) and endothelial cells (Suhara et al, 2003). Akt downregulation increases GSK-3␤ activity, which in turn may favor conditions that promote neuronal death, tau aggregation, and ␤-catenin destabilization (Hanger et al, 1992;Aberle et al, 1997;Crowder and Freeman, 2000;Hetman et al, 2000;Alvarez et al, 2004), all of them reported to be important features in AD pathogenesis.…”

Heat Shock Protein 70 Participates in the Neuroprotective Response to Intracellularly Expressed β-Amyloid in Neurons

“…Different mechanisms have been proposed to explain neurodegeneration, for instance the p53, JNK, and PI3K/Akt signaling pathways are reported to be affected by intracellular A␤ (LaFerla et al, 1996;Shoji et al, 2000;Zhang et al, 2002;Suhara et al, 2003). However, increasing evidence points to a role for molecular chaperones in these neurodegenerative processes (Bonini, 2002;Sakahira et al, 2002).…”

“…A␤42 peptide appears to be the prominent form that accumulates inside neurons in AD brains and in transgenic mice expressing familial AD mutations (Takahashi et al, 2002a). However, only a limited number of reports have specifically studied the intracellular effects of A␤42 peptide accumulation using either transgenic animals (LaFerla et al, 1995;Link, 1995) or non-neuronal cell lines (Johnstone et al, 1996;Querfurth et al, 2001;Suhara et al, 2003). Recently, delivery of A␤ synthetic peptides into neurons by microinjection has been reported (Zhang et al, 2002).…”