Chronic ghrelin administration suppresses IKK/NF-κB/BACE1 mediated Aβ production in primary neurons and improves cognitive function via upregulation of PP1 in STZ-diabetic rats

Autor: Song-Fang Liu, Louyan Ma, Peng-Fei Hou, Qing Shu, Ran-Ran Ma, Jun-Hui Du, Ya-Li Lv, Qiu-Min Qu, Yu Niu, Songdi Wu
Rok vydání: 2019
Předmět:
Male
medicine.medical_specialty
Cognitive Neuroscience
Morris water navigation task
Experimental and Cognitive Psychology
Hippocampal formation
environment and public health
Hippocampus
050105 experimental psychology
Streptozocin
Diabetes Mellitus
Experimental
Rats
Sprague-Dawley
03 medical and health sciences
Behavioral Neuroscience
0302 clinical medicine
Cognition
Downregulation and upregulation
Internal medicine
Protein Phosphatase 1
medicine
Hippocampus (mythology)
Animals
Aspartic Acid Endopeptidases
0501 psychology and cognitive sciences
Cells
Cultured
Neurons
Amyloid beta-Peptides
Chemistry
digestive
oral
and skin physiology
05 social sciences
Antagonist
NF-kappa B
Protein phosphatase 1
Streptozotocin
Ghrelin
I-kappa B Kinase
Up-Regulation
enzymes and coenzymes (carbohydrates)
Endocrinology
Synapses
biological phenomena
cell phenomena
and immunity
Amyloid Precursor Protein Secretases
Neuroscience
030217 neurology & neurosurgery
medicine.drug
Signal Transduction
Zdroj: Neurobiology of learning and memory. 169
ISSN: 1095-9564
Popis: Diabetic rats display cognition impairments accompanied by activation of NF-κB signalling and increased Aβ expression. Ghrelin has been suggested to improve cognition in diabetic rats. In this study, we investigated the role of ghrelin on cognition and NF-κB mediated Aβ production in diabetic rats. A diabetic rat model was established with streptozotocin (STZ) injection, and diabetic rats were intracerebroventricularly administered with ghrelin or (D-lys3)-GHRP-6 (DG). Our results showed that diabetic rats had cognition impairment in the Morris water maze test, accompanied by the higher expression of Aβ in the hippocampus. Western blot analysis showed that diabetic rats exhibited significantly decreased levels of GHSR-1a and protein phosphatase 1 (PP1) in the hippocampus and increased activation of the IKK/NF-κB/BACE1 pathway. Chronic ghrelin administration upregulated hippocampal PP1 expression, suppressed IKK/NF-κB/BACE1 mediated Aβ production, and improved cognition in STZ-induced diabetic rats. These effects were reversed by DG. Then, primary rat hippocampal neurons were isolated and treated with high glucose, followed by Ghrelin and DG, PP1 or IKK. Similar to the in vivo results, high glucose suppressed the expression levels of GHSR-1a and PP1, activated the IKK/NF-κB/BACE1 pathway, increased Aβ production. Ghrelin suppressed IKK/NF-κB/BACE1 induced Aβ production. This improvement was reversed by DG and a PP1 antagonist and was enhanced by the IKK antagonist. Our findings indicated that chronic ghrelin administration can suppress IKK/NF-κB/BACE1 mediated Aβ production in primary neurons with high glucose treatment and improve the cognition via PP1 upregulation in diabetic rats.
Databáze: OpenAIRE
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