Amyloid-β oligomers synaptotoxicity: The emerging role of EphA4/c-Abl signaling in Alzheimer's disease

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1864

Review

Vargas, L. M.¹  Cerpa, W.²  Munoz, F. J.⁴  Zanlungo, S.³  Alvarez, A. R.¹ 

[1] Pontificia Univ Catolica Chile, Biol Sci Fac, Ctr UC Envejecimiento & Regenerac CARE, Dept Cellular & Mol Biol,Cell Signaling Lab, Santiago, Chile

[2] Pontificia Univ Catolica Chile, Biol Sci Fac, Dept Cellular & Mol Biol, Pathol & Neuronal Funct Lab, Santiago, Chile

[3] Pontificia Univ Catolica Chile, Fac Med, Dept Gastroenterol, Santiago, Chile

[4] Univ Pompeu Fabra, Lab Mol Physiol & Channelopathies, Barcelona, Spain

关键词: Synaptotoxicity;    EphA4;    c-Abl;    Alzheimer's disease;    A beta oligomers;   

DOI  :  10.1016/j.bbadis.2018.01.023

来源: Elsevier

【 摘 要 】

Alzheimer's disease (AD) is characterized by progressive memory loss and dementia. The strong correlation between cognitive decline and the loss of synapses supports the idea that synaptic damage is a relevant pathogenic mechanism underlying AD progression. It has been shown that amyloid beta oligomers (A beta Os) induce synaptotoxicity ultimately leading to the reduction of dendritic spine density, which underlies cognitive damage. However, the signaling pathways connecting A beta Os to synaptic dysfunction have not been completely elucidated. In this review, we have gathered evidence on A beta Os receptors and the signaling pathways involved in synaptic damage. We make special emphasis on a new A beta Os induced axis that involves the tyrosine kinase ephrin receptor A4 (EphA4) and c-Abl tyrosine kinase activation. EphA4 is a key player in homeostatic plasticity, mediating dendritic spine remodeling and retraction. A beta Os aberrantly activate EphA4 leading to dendritic spine elimination. c-Abl is activated in A beta Os exposed neurons and in AD patient's brain, and the inhibition of activated c-Abl ameliorates cognitive deficits in AD mouse model. The EphA4 receptor activates c-Abl intracellular signaling. Therefore EphA4 is an emerging A beta Os receptor and the activation of the EphA4/c-Abl axis would explain the synaptic spine alterations found in AD.

【 授权许可】

Free