DNA damage-inducing agents elicit γ-secretase activation mediated by oxidative stress

Abstract

According to the amyloid cascade hypothesis, Alzheimer's disease is the consequence of neuronal cell death induced by b-amyloid (Ab), which accumulates by abnormal clearance or production. On the other hand, recent studies have shown cell death-induced alteration in amyloid precursor protein (APP) processing, suggesting potential mutual interactions between APP processing and cell death. We have shown previously that the cell death caused by DNA damage-inducing agents (DDIAs) facilitated c-secretase activity and Ab generation in a Bax/Bcl-2-dependent, but caspase-independent manner. Here, we attempted to elucidate the downstream mechanism that modulates c-secretase activity in DDIA-treated cells. N-acetyl cysteine, a potent antioxidant, attenuated DDIA-induced enhancement of c-secretase activity but failed to rescue cell death. Overexpression of heat shock protein 70, which blocks cytochrome c release from mitochondria, also reduced c-secretase activity. Moreover, glutathione depletion significantly facilitated c-secretase activity and Ab generation by enhancing the formation of higher molecular weight c-secretase complex before signs of cell death developed. Finally, Ab treatment, a known inducer of oxidative stress, also increased c-secretase activity. Taken together, these results indicate that DDIA-induced c-secretase activation is dependent on augmented oxidative stress, and that Ab and c-secretase may activate each other. On the basis of these results, we propose a feed-back loop between oxidative stress and Ab generation mediated by c-secretase activation.

RAGE regulates BACE1 and Aβ generationviaNFAT1 activation in Alzheimer's disease animal model

“…Aβ levels were measured by a sandwich ELISA kit using an anti‐Aβ N‐terminal antibody and an anti‐Aβ40 or Aβ42 C‐terminal antibody, according to the manufacturer's instructions (Biosource International, Camarillo, CA). To detect the level of Aβ released from cultured cells, conditioned medium (CM) was collected from primary cortical culture of Tg2576 mouse brains and subjected to the sandwich ELISA kit (21, 22).…”

The Arsenic Exposure Hypothesis for Alzheimer Disease

“…129 Exposure to environmental arsenic (5 to 20 mg/L and 10 to 50 mg/L in drinking water in humans and mice, respectively) increases oxidative damage to DNA and proteins not secondary to inflammatory responses. [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] However, clinical trials on the effects of antioxidants such as vitamins C and E on AD prevention and progression are mixed or unimpressive. [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] However, clinical trials on the effects of antioxidants such as vitamins C and E on AD prevention and progression are mixed or unimpressive.…”

Critical role of presenilin-dependent γ-secretase activity in DNA damage-induced promyelocytic leukemia protein expression and apoptosis

“…Interestingly, PML is itself a p53 target gene that also acts downstream of p53 to potentiate its antiproliferative effects, 19 representing the positive-feedback Our previous study indicated that genotoxic stressors such as CPT and etoposide enhance g-secretase activity and Ab generation mediated by oxidative stress. 7,8 As PS is a major catalytic core in the g-secretase complex, it might act as a possible mediator between g-secretase activity and DNAdamaged apoptotic signaling via p53 tumor suppressor proteins. Recently, it was reported that AICD together with Fe65 and Tip60 (AFT complex) showed a close physical apposition in PML-NB bodies.…”

“…PML protein and PML mRNA level are upregulated in human AD brains. We previously reported that Ab treatment upregulates g-secretase activity in cell culture systems 7 and recent study reported that g-secretase activity might be upregulated in human AD brains. 20 As PML expression was regulated by g-secretase activity, we further hypothesized that PML expression might be elevated in human AD patients.…”

“…5 Moreover, PML has been found to physically associate with critical apoptosis regulators including p53, pRb, c-Jun and Daxx. 6 Our previous studies have shown that genotoxic stressors such as camptothecin (CPT) and etoposide enhance g-secretase activity and Ab generation, 7,8 suggesting that modulation of g-secretase activity is a component of the genotoxic cell death pathway. As presenilin (PS) contains the core catalytic activity within the g-secretase complex, we hypothesized that PS has a key role in mediating DNA damage-induced cell death.…”