Raf inhibition protects cortical cells against beta-amyloid toxicity
Valentina Echeverria1, Sarah Burgess, Joyonna Gamble-George
1Bay Pines VA Healthcare System, Bay Pines, FL 33744, USA. valentina.echeverria@va.gov
Abstract:
Alzheimer's disease (AD) is the main cause of dementia in the elderly. The discovery of new targets of therapeutic intervention is fundamental to the development of new drugs against AD pathology. Upregulation of cRaf-1 has been found post-mortem in the brains of AD patients. cRaf-1 is a cytosolic protein kinase that regulates neuronal survival and senescence. In this study, we investigated cRaf-1 in the brains of aged APPswe mice presenting AD-like pathology and whether Raf inhibitors protected cultured cortical cells against amyloid beta toxicity (Abeta). We found a dysregulation of cRaf-1 in the cortex of APPswe mice, which showed a 147% increase in the active form phosphorylated at serine 338 and a 40% decrease in the levels of the inactive form of cRaf-1, phospho-cRaf-1[Ser259]. Furthermore, treatment of primary cortical neurons with the cRaf-1 inhibitors, GW5074 or ZM336372, and the nuclear factor kappa B (NFkappaB) inhibitor SN50, protected cortical neurons against Abeta toxicity. Since Raf stimulates NFkappaB, we studied the effect of Raf inhibition on its activation by studying changes in NFkappaB phosphorylation at serine 276. Our results suggest that Raf inhibition with GW5074 is neuroprotective against Abeta toxicity through a mechanism that involves NFkappaB inhibition.
Insights
Researchers found that inhibiting c-Raf-1 kinase in mouse models of Alzheimer's disease (AD) protected neurons from amyloid beta toxicity, suggesting a new therapeutic target for AD pathology.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Alzheimer's disease (AD) is a leading cause of dementia, necessitating novel therapeutic targets.
- Upregulation of c-Raf-1, a protein kinase regulating neuronal survival, has been observed in AD brains.
- Amyloid beta (Abeta) toxicity is a key factor in AD pathology.
Purpose of the Study:
- To investigate the role of c-Raf-1 in an AD mouse model.
- To determine if c-Raf-1 inhibitors offer neuroprotection against Abeta toxicity.
- To explore the mechanism involving nuclear factor kappa B (NFkappaB) signaling.
Main Methods:
- Analysis of c-Raf-1 expression and activation in APPswe mice brains.
- Treatment of primary cortical neurons with c-Raf-1 inhibitors (GW5074, ZM336372) and an NFkappaB inhibitor (SN50).
- Assessment of neuronal survival against Abeta toxicity and measurement of NFkappaB phosphorylation.
Main Results:
- Dysregulation of c-Raf-1 observed in APPswe mice, with increased active phosphorylated c-Raf-1 (Ser338) and decreased inactive form (p-c-Raf-1[Ser259]).
- GW5074, ZM336372, and SN50 demonstrated neuroprotective effects against Abeta toxicity in cultured neurons.
- Raf inhibition with GW5074 reduced NFkappaB activation, indicated by decreased NFkappaB phosphorylation at Ser276.
Conclusions:
- c-Raf-1 dysregulation is implicated in AD-like pathology in mice.
- Inhibition of c-Raf-1 provides neuroprotection against Abeta-induced toxicity.
- The neuroprotective mechanism involves the inhibition of NFkappaB signaling pathway.
