An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling

Abstract

A missense mutation (T835M) in the uncoordinated-5C (UNC5C) netrin receptor gene increases the risk of late-onset Alzheimer disease (AD) and also the vulnerability of neurons harboring the mutation to various insults. The molecular mechanisms underlying T835M-UNC5C-induced death remain to be elucidated. In this study, we show that overexpression of wildtype UNC5C causes low-grade death, which is intensified by an AD-linked mutation T835M. An AD-linked survival factor, calmodulin-like skin protein (CLSP), and a natural ligand of UNC5C, netrin1, inhibit this death. T835M-UNC5C-induced neuronal cell death is mediated by an intracellular death-signaling cascade, consisting of death-associated protein kinase 1/protein kinase D/apoptosis signal-regulating kinase 1 (ASK1)/ JNK/NADPH oxidase/caspases, which merges at ASK1 with a death-signaling cascade, mediated by amyloid ␤ precursor protein (APP). Notably, netrin1 also binds to APP and partially inhibits the death-signaling cascade, induced by APP. These results may provide new insight into the amyloid ␤-independent pathomechanism of AD.

β-Ecdysterone protects SH-SY5Y cells against β-amyloid-induced apoptosis via c-Jun N-terminal kinase- and Akt-associated complementary pathways

“…As depicted in Fig. 2e, β-Ecd attenuated release of cyt c induced by Aβ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). As shown in Fig.…”

“…Aβ 1-42 is the major peptide constituent of amyloid plaques. Aβ [25][26][27][28][29][30][31][32][33][34][35] , though not present in biological systems, is found to be at least as toxic as the full-length fragment. Therefore, Aβ 25-35 is widely used together with, or instead of, the endogenous fragment Aβ 1-42 in AD-relevant insults in vitro [35].…”

“…4a, b, β-Ecd inhibits JNK phosphorylation induced by Aβ. Given that ASK1 acts as an upstream regulator for the activation of JNK in brain of patients with AD [30], we next investigated whether β-Ecd inhibits ASK1 activation in Aβ-challenged SH-SY5Y cells. As expected, Aβ-induced ASK1 phosphorylation (that is, activation) in SH-SY5Y cells was attenuated by β-Ecd (Fig.…”

“…5d, e indicate that JNK or ROS is a prerequisite for the downregulation of Bax by β-Ecd, because β-Ecd-mediated inhibition of Bax is exclusively inhibited by the JNK inhibitor SP600125 well as a NADPH oxidase inhibitor DPI in SH-SY5Y cells exposed to Aβ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). The Akt inhibitor LY294002 did not diminish the Bax downregulation in SH-SY5Y cells exposed to Aβ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). These results suggest that the activation of the Akt and inhibition of JNK signaling pathways by β-Ecd are mediated by independent mechanisms.…”

FANCC localizes with UNC5A at neurite outgrowth and promotes neuritogenesis

“…Furthermore, significant expression changes in UNC5A were found in the posterior cingulate brain region of AD patients, while mutations in UNC5C seemed to predispose to late-onset Alzheimer’s disease [ 29 – 31 ]. These data suggest a link between FANCC, the axon-guidance pathway and Alzheimer’s disease thus further highlighting the importance of UNC5A and FANCC in cell death signaling in health and disease conditions.…”