Research Article: Prevention of β-amyloid degeneration of microglia by erythropoietin depends on Wnt1, the PI 3-K/mTOR pathway, Bad, and Bcl-xL

Date Published: March 3, 2012

Publisher: Impact Journals LLC

Author(s): Yan Chen Shang, Zhao Zhong Chong, Shaohui Wang, Kenneth Maiese.



Central nervous system microglia promote neuronal regeneration and sequester toxic β-amyloid (Aβ) deposition during Alzheimer’s disease. We show that the cytokine erythropoietin (EPO) decreases the toxic effect of Aβ on microgliain vitro. EPO up-regulates the cysteine-rich glycosylated wingless protein Wnt1 and activates the PI 3-K/Akt1/mTOR/ p70S6K pathway. This in turn increases phosphorylation and cytosol trafficking of Bad, reduces the Bad/Bcl-xL complex and increases the Bcl-xL/Bax complex, thus preventing caspase 1 and caspase 3 activation and apoptosis. Our data may foster development of novel strategies to use cytoprotectants such as EPO for Alzheimer’s disease and other degenerative disorders.

Partial Text

More than twenty-five million individuals may suffer from Alzheimer’s disease, pre-senile dementia, and other disorders of cognitive loss throughout the world [1, 2]. β-amyloid (Aβ) deposition in the brain is considered to be a significant component of Alzheimer’s disease that leads to progressive neuro-degeneration. Aβ toxicity can involve multiple cell types including neurons [3-6], vascular cells [2, 7, 8], and inflammatory microglial cells [7, 9]. In regard to microglia, these inflammatory cells can form a protective network for the brain to control neurotrophic factors [10], limit oxidative stress [11, 12], and foster neuronal regeneration [13]. Microglia also may limit the deposition and toxicity of Aβ and promote neuronal survival [4, 9, 14-16].

Therapeutic strategies that target the accumulation and toxicity of Aβ in the brain during Alzheimer’s disease may offer significant promise for the treatment of this neurodegenerative disorder [2, 5, 58]. In particular, focus upon central nervous system microglia, immune cell sentinels that can sequester Aβ[4, 9, 14-16], may offer great promise for new therapies. Furthermore, identification of microglial cytoprotective pathways for entities such as EPO and Wnt1 [59-61] may synergistically enhance the development of treatments for Alzheimer’s disease.





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