Proposed mechanisms by which c-Fos contribute to neuroprotection or neurodegeneration outcome in hippocampus (IMAGE)
Caption
Neural activity in healthy brain releases glutamate which binds to synaptic receptors and activates Ca++ influx and further signaling pathways of CAM/ERK/MAPK/CREB in neurons. CREB elevation leads in memory improvement via expression of c-Fos, and BDNF. Then the FOS protein is returns to the nucleus and acts together with c-Jun by binding and forming the activator protein-1 (AP-1) heterodimer, and leads in long term memory. On the other hand, hyper activation of extra synaptic NMDA receptors elevates ROS and Aβ toxicity, and increase transcription of c-Fos. The expressed c-Fos protein is additionally stabilized by Aβ42-induced O-GlcNAcylation, and the glycosylated c-Fos binds with c-Jun stimulates neuronal cell death by activating the apoptotic factor Bim, ATF3 and cytochrome c, besides, it downregulates CREB and BDNF which leads in memory impairment. AD, Alzheimer’s disease; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; AP-1, activator protein-1; ATF, activation transcription factor; Aβ, amyloid beta; BDNF, brain derived neurotrophic factor; BIM, B-cell lymphoma 2 interacting mediator of cell death; CREB, cAMP response element binding; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; NMDA, N-methyl-D-aspartate; PKA, protein kinase A; PKC, protein kinase C; RAF, rapidly accelerated fibrosarcoma kinase.
Credit
Parvin Babaei
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