Premium
P1‐003: The prolonged high‐fat dietary impairs functional neuronal insulin sensitivity in hippocampus
Author(s) -
Chattipakorn Siriporn,
Pratchayasakul Wasana,
Petsophonsakul Petnoi,
Pongchaidacha Anchalee,
Chattipakorn Nipon
Publication year - 2009
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2009.04.006
Subject(s) - insulin resistance , medicine , endocrinology , insulin , insulin receptor , hippocampus , hippocampal formation , biology
Background: Alzheimer’s disease is a progressive neurodegenerative disorder clinically characterized by loss of memory and deficits in cognitive and intellectual functions. Steadily developing damage to the neural networks critical for memory and learning possibly underlies the devastating symptomatology. In Alzheimer’s, the hippocampus is the area that shows the most atrophy. Recent evidence suggested circulating ghrelin promoted dendritic spine synapse formation and long-term potentiation in the hippocampus by crossing the blood-brain barrier. The ghrelin-induced synaptic changes were paralleled by enhanced spatial learning and memory. However, the cellular signaling mechanisms underlying the ghrelin’s neurogenerative and stimulative effects are not completely understood. We investigated the effect of ghrelin on the phosphorylation of CREB (c-AMP response element binding protein), the transcription factor that consolidates memories by inducing gene expression and protein synthesis. Methods: In cultured hippocampal slices, CREB activities and the phosphorylation of CREB (pCREB) were assayed immunohistochemically using anti-pCREB antibody (Ser133) and fluorescence-tagged secondary antibody. pCREB expression was analyzed with a confocal microscope and quantified as a ratio between total CREB vs. pCREB. Results: Ghrelin receptor (GHSR) was highly expressed in our hippocampal slice culture. In vitro application of ghrelin to cultured hippocampal slices up-regulated pCREB expression in a dose-dependent manner in isolation of extrahippocampal synaptic contacts. This finding was supported by our in vivo animal model of fasting. Fasting up-regulates the plasma ghrelin level. In the fasted rats, the expression of pCREB was increased in the hippocampus. The present results suggest that ghrelin may enhance hippocampal neuron growth and plasticity by stimulating CREB activities. Conclusions: We conclude that ghrelin stimulates phosphorylation of CREB in the hippocampus. The phosphorylated CREB could be a key molecule to exert the ghrelin’s effect of promoting synaptic formation and functions as well as of protecting hippocampal neurons from degeneration. There is a strong link between the progression of dementia, like in Alzheimer’s disease, and Type II diabetes in which ghrelin level is reduced. Our results suggest exogenous administration of ghrelin centrally to the hippocampus or therapeutic restoration of circulating ghrelin levels (such as caloric restriction) may contribute towards the treatment and prevention of age-related cognitive decline and dementia in the Alzheimer’s disease.