September 22, 2017 17:00 - 18:00
BSI Central Building 3F Seminar Room
Experimental evidence suggests that metabolic imbalance associated with obesity and diabetes negatively impacts on cognitive function, increases the risk for neurodegenerative diseases and accelerates brain aging through molecular and cellular mechanisms not fully elucidated yet. To address this issue we investigated the effects of high glucose levels and brain insulin resistance produced by high-fat diet (HFD) on adult hippocampal neurogenesis and hippocampal synaptic plasticity.
First, we identified a glucose-regulated antagonism between CREB and Sirt1 for Hes1 transcription that is critically involved in the metabolic regulation of neurogenesis. Specifically, we found that high glucose levels markedly inhibited neural stem cell (NSC) proliferation via Sirt1-mediated decrease of histone 3 lysin 9 (H3K9) acetylation at the promoter of the Hes1 gene. Conversely, in low glucose, the complex CREB-CBP replaced Sirt1 on the chromatin associated with the Hes1 promoter thereby increasing Hes1 expression and NSC proliferation.
With reference to hippocampal synaptic plasticity, we identified a novel molecular cascade triggered by brain insulin resistance and leading to aberrant palmitoylation of GluR1 AMPA receptor subunit, that plays a critical role in both hippocampal synaptic plasticity impairment and cognitive decline observed in experimental models of metabolic diseases. Specifically, the HFD-induced brain insulin resistance increased the expression of the palmitoyl-transferase Zdhhc3 via both enhanced binding of the transcription factor FoxO3a and increased H3H9 acetylation on the regulatory sequences of this gene. Overexpression of Zdhhc3 caused hyper-palmitoylation and hypo-phosphorylation of GluR1, thus hindering its activity-dependent trafficking to the plasma membrane. Consequently, AMPA currents and, more importantly, their potentiation underlying synaptic plasticity were inhibited thereby impairing hippocampal-dependent memory.
Collectively, our findings suggest that hippocampal plasticity and hippocampal-dependent memory are markedly impaired by metabolic signals associated with poor diet, thus highlighting tight links between metabolic and neurodegenerative diseases.
- Open to Public
- Toru TAKUMI [Toru Takumi, Mental Biology ]
Name: Toru TAKUMI