Abstract
Apoptosis signal-regulating kinase 1–interacting (ASK1-interacting) protein-1 (AIP1) is a newly identified novel member of the Ras GTPase-activating protein family, which has been implicated in cell growth inhibition and cell apoptosis. However, the effects of AIP1 in Alzheimer’s disease (AD) are unknown. In the present study, we found that AIP1 was elevated in the brain of AD Tg2576 mice and Aβ1-42 treated brain cerebral microvascular endothelial cells (CECs). Aβ1-42 treatment induced the interaction of AIP1 and apoptosis signal-regulating kinase 1 (ASK1), which led to dissociation of ASK1 and its inhibitor 14-3-3. Dissociation of ASK1 from 14-3-3 leads to ASK1 activation. Indeed, Aβ1-42 dephosphorylated ASK1 at Ser-967, suggesting that Aβ1-42 increased ASK1 activity. Importantly, disassociation of ASK1 and 14-3-3 induced by Aβ1–42 could be rescued by silence of AIP1. In addition, down-regulation of AIP1 also led to attenuation of the activation of JNK, as well as p53, downstream signaling targets of ASK1. AIP1 silencing attenuated the pro-apoptotic effects of Aβ1-42 on CECs. We propose that AIP1 mediates Aβ induced ASK1 activation by facilitating dissociation of 14-3-3, suggesting a novel mechanism for Aβ-induced apoptosis in CECs.
Highlights
Alzheimer's disease (AD) is neuropathologically characterized by intracellular neurofibrillary tangles (NFTs) and extracellular senile plaques (Roberson and Mucke 2006)
In order to examine whether the expression of AIP1 was changed in AD, we investigated the expression levels of AIP1 in the brains of Tg2576 mice at messenger RNA levels and protein levels
As Aβ was extensively associated with vascular endothelium dysfunction in AD, we investigated the effect of Aβ1-42 in the expression of AIP1 in human primary cerebral endothelial cells (CECs)
Summary
Alzheimer's disease (AD) is neuropathologically characterized by intracellular neurofibrillary tangles (NFTs) and extracellular senile plaques (Roberson and Mucke 2006). The main component of extracellular senile plaques is βamyloid (Aβ) (Buoso et al 2010). Multiple lines of evidence suggest that Aβ induces apoptosis in neurons, and in cerebral endothelial cells (CECs) (Yin et al 2002). CECs play a critical role in blood–brain barrier (BBB) to shield the brain from damage by harmful circulating toxins or deleterious cellular elements. Aβ deposition in cerebrovascular surface forms cerebral amyloid angiopathy (CAA), which has been proved to play a critical role in the progress of AD (Yamada and Naiki 2012). CEC apoptosis appears to be a contributing factor in Aβ-induced cerebrovascular degeneration. The mechanisms underlying the CEC apoptosis are still needed to be elucidated
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