TNF-α mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer's ß-amyloid oligomers in mice and monkeys.
Cell Metab
; 18(6): 831-43, 2013 Dec 03.
Article
in En
| MEDLINE
| ID: mdl-24315369
ABSTRACT
Alzheimer's disease (AD) and type 2 diabetes appear to share similar pathogenic mechanisms. dsRNA-dependent protein kinase (PKR) underlies peripheral insulin resistance in metabolic disorders. PKR phosphorylates eukaryotic translation initiation factor 2α (eIF2α-P), and AD brains exhibit elevated phospho-PKR and eIF2α-P levels. Whether and how PKR and eIF2α-P participate in defective brain insulin signaling and cognitive impairment in AD are unknown. We report that ß-amyloid oligomers, AD-associated toxins, activate PKR in a tumor necrosis factor α (TNF-α)-dependent manner, resulting in eIF2α-P, neuronal insulin receptor substrate (IRS-1) inhibition, synapse loss, and memory impairment. Brain phospho-PKR and eIF2α-P were elevated in AD animal models, including monkeys given intracerebroventricular oligomer infusions. Oligomers failed to trigger eIF2α-P and cognitive impairment in PKR(-/-) and TNFR1(-/-) mice. Bolstering insulin signaling rescued phospho-PKR and eIF2α-P. Results reveal pathogenic mechanisms shared by AD and diabetes and establish that proinflammatory signaling mediates oligomer-induced IRS-1 inhibition and PKR-dependent synapse and memory loss.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Polymers
/
Brain
/
Amyloid beta-Peptides
/
Tumor Necrosis Factor-alpha
/
EIF-2 Kinase
/
Insulin Receptor Substrate Proteins
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Cell Metab
Journal subject:
METABOLISMO
Year:
2013
Type:
Article
Affiliation country:
Brazil