Apoptosis Signal-Regulating Kinase 1 in Amyloid β Peptide-Induced Cerebral Endothelial Cell Apoptosis

Abstract

A pathological hallmark of Alzheimer's disease is accumulation of amyloid-␤ peptide (A␤) in senile plaques. A␤ has also been implicated in vascular degeneration in cerebral amyloid angiopathy because of its cytotoxic effects on non-neuronal cells, including cerebral endothelial cells (CECs). We explore the role of apoptosis signal-regulating kinase 1 (ASK1) in A␤-induced death in primary cultures of murine CECs. A␤ induced ASK1 dephosphorylation, which could be prevented by selective inhibition of protein phosphatase 2A (PP2A) but not PP2B. ASK1 dephosphorylation resulted in its dissociation from 14-3-3. ASK1, released from 14-3-3 inhibition, activated p38 mitogen-activated protein kinase (p38MAPK), leading to p53 phosphorylation. p53, a proapoptotic transcription factor, in turn transactivated the expression of Bax, a proapoptotic protein. Transfection with various dominant-negative mutants (DNs), including ASK1 DN and p38MAPK DN, suppressed A␤-induced p38MAPK activation, p53 phosphorylation, and Bax upregulation and partially prevented CEC death. Bax knockdown using a bax small interfering RNA strategy also reduced Bax expression and subsequent CEC death. These results suggest that A␤ activates the ASK1-p38MAPK-p53-Bax cascade to cause CEC death in a PP2A-dependent manner.

A novel bioactivity of andrographolide fromAndrographis paniculataon cerebral ischemia/reperfusion-induced brain injury through induction of cerebral endothelial cell apoptosis

“…Mouse CECs were prepared as described previously (Hsu et al, 2007). Briefly, the gray matter of fresh mouse brains was homogenized and filtered, and the resulting fraction was then sequentially digested with 4 mg/mL collagenase B for 2 h and 1 mg/mL collagenase/dispase (Roche Molecular Biochemicals, Indianapolis, IN) for 2 h, followed by centrifugation in a 40% Percoll solution.…”

“…Cheng et al (2003) demonstrated that ischemia-induced apoptosis of CECs was mediated by increased expression of p53 and activation of caspase-3 signaling. Deposition of b-amyloid (Ab) also induced CEC death via caspase-8/reactive oxygen species (ROS)/apoptosis signal-regulating kinase 1 (ASK)1-dependent apoptosis (Hsu et al, 2007;Xu et al, 2001). Therefore, protection of the BBB from apoptosis may be a beneficial therapeutic strategy for neuronal functions.…”

Role of Apoptosis Signal-regulating Kinase 1 (ASK1) as an Activator of the GAPDH-Siah1 Stress-Signaling Cascade

“…In addition, ASK1 plays pivotal roles in a wide variety of cellular responses, which include, but are not limited to, apoptosis (30,31). Dysregulation of the ASK1 signaling pathway is closely linked to various diseases, such as cancer, cardiovascular diseases, diabetes, and neurodegenerative diseases including polyglutamine-induced neurodegeneration and Parkinson disease (29,(32)(33)(34)(35)(36)(37).…”

ASK1 and Its Role in Neurodegenerative Diseases

“…Upon TNFα treatment the AIP1/PP2A complex was found to interact with and dephophorylate ASK1 at Ser967, leading to the dissociation of its inhibitor 14-3-3 and ASK1 activation [49]. Furthermore, Aβ was found to induce ASK1 Ser967 dephosphorylation and its dissociation from the 14-3-3 protein leading to p38 activation, and induction of the pro-apoptopic BCl-2 family member, Bax [50]. Selective inhibition of PP2A prevented the activation of this signaling cascade linking ASK1 Ser967 phosphorylation status to Aβ-induced toxicity.…”

“…These data strongly suggest that ASK1 could play a significant role in the pathogenesis of AD by mediating ROS and/or Aβ induced neuronal cell death via the MKK6/JNK/p38 pathway. In addition, Aβ was not only shown to cause neuron-specific toxicity, but also demonstrated to cause vascular degeneration in cerebral amyloid angiopathy; Hsu and coworkers employed primary murine cerebral endothelial cells (CEC) to investigate the mode of cell death mediated by Aβ in ASK1 transfected CECs [50]. Aβ exposure was observed to result in an induction of the ASK1-MKK3/6-p38-p53 signaling machinery and increased levels of the pro-apoptotic protein Bax resulting in CEC programmed cell death.…”