The accumulation of amyloid peptide (Aβ) and subsequent neural plaques formation are implicated in the pathogenesis of Alzheimer’s disease (AD). Vascular amyloid deposition leads to the development of cerebral amyloid angiopathy (CAA). CAA is an age-dependent degeneration of cerebral vasculature, leading to increased vulnerability to hemorrhagic and ischemic strokes in the elderly. The molecular mechanism underlying Aβ-induced vasculopathy has not been fully delineated. Aβ was reported causing apoptosis in cerebral endothelial cells (CECs). Our recently study demonstrated that Aβ-induced p53 phosphorylation and activation is secondary to the activation of ASK1-MKK3/6-p38MAPK signaling cascade, which in turn induces Bax expression and subsequent CEC apoptosis. p53 has been implicated as a key regulator of neuronal apoptosis in response to neuropathological and neurodegenerative conditions. In addition to phosphorylation, acetylation of p53 also activates transcription of downstream targets with proapoptotic properties. Therefore, the acetylation status of p53 may be crucial for cell life and death decisions. In addition to histone¸ histone deacetylase (HDAC) that downregulates the acetylation levels of many regulatory proteins involved in energy homeostasis, cell survival and lifespan extension. HDACs such as sirtuin is expressed predominantly in developing nervous systems. Recent study further demonstrated that sirtuin overexpression confers a significant protection against neurodegeneration in models for AD. Whether HDACs including sirtuin plays an essential role in Aβ-induced non-neuronal cell death remains to be established. In our preliminary studies, we found that Aβ time-dependently increased p53 acetylation in CECs. Phosphorylation of AMPK, which was recently reported to downregulated HDAC, was increased in CECs after Aβ exposure. However, the molecular mechanisms involved in Aβ-induced p53 acetylation and the role of AMPK and HDAC in Aβ apoptotic action are still largely unknown. This project aims to establish the causal role of AMPK in Aβ-induced HDAC inactivation and p53 acetylation in CECs. Establishing the Aβ- AMPK-HDAC-p53 cascade will greatly broaden our insight into the understanding of the death signaling pathway and aid in future development of preventive strategies to slow down age-dependent cerebral vascular degeneration and reduce stroke risk in the elderly. The central hypothesis of this project is that Aβ, which accumulates in cerebral blood vessels in CAA, downregulates HDAC resulting in p53 acetylation and activation to elevate Bax and cell death.
|Effective start/end date||8/1/10 → 7/31/11|