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Joslin Diabetes Center - Boston
Targeting PKM2 in chronic hypoperfusion for the treatment of cognitive impairment in type 2 diabetes
Type 2 diabetes (T2D) is associated with morphologic changes in brain structure, including brain atrophy, white matter lesions, hypoperfusion and stroke leading to cognitive changes mainly affecting learning and memory. Although the causes for vascular cognitive impairment and dementia (VCID) are not clear, increasing evidence suggests cerebral hypoperfusion is the dominant pathogenic process. There is an urgent need to understand the mechanisms involved and the development of new therapeutic strategies to reverse the cognitive decline. Recent studies have indicated that pyruvate kinase M2 (PKM2) mediated signaling plays a crucial role, not only in regulating glycolysis, but also in many cellular functions including proliferation, inflammation and mitochondrial stress. Furthermore, oxidative metabolism in different cells contributes significantly to the pathogenesis of T2D. The role of metabolism in astrocyte function is not well studied, and the role of astrocytes in T2D pathogenesis of VCID is completely unknown. We hypothesize that disturbance of PKM2 signaling in astrocyte cells underlies the pathogenesis of VCID in T2D. To test this hypothesis, we have generated an animal model of cognitive impairment-induced by chronic hypoperfusion in T2D. Our preliminary data show an increase in PKM2 protein levels and a decrease in enzymatic activity in hippocampus of VCID mice with T2D, indicating a novel molecular mechanism mediated by glucose metabolism in cognitive decline. Moreover, VCID mice with T2D induce PKM2 translocation to the nucleus and an increased nuclear HIF-1alpha expression in the hippocampus. These perturbations were followed by high levels of several inflammatory markers in the hippocampus. In this proposal, we will use a conditional PKM2 knockout in astrocytes and a pharmacological PKM2 activator to test our hypothesis by addressing the following questions: (1) whether PKM2 in astrocytes contributes to the overall metabolic disorders that underlies the pathogenesis of cognitive decline, blood brain barrier leakage and inflammation evident in VCID mice with T2D; and (2) whether a PKM2 activator may represent a therapeutic strategy against VCID mice with T2D. Collectively, these studies will determine how PKM2 in astrocytes contributes to cognitive decline in T2D, and how PKM2 affects brain inflammation and permeability, and glucose metabolism in VCID mice with T2D. Ultimately, we will test if a PKM2 activator is a novel therapeutic strategy for VCID patients with T2D.
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Targeting PKM2 in chronic hypoperfusion for the treatment of cognitive impairment in type 2 diabetes (Simao, Fabricio)
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Please acknowledge all posters, manuscripts or scientific materials that were generated in part or whole using funds from the Diabetic Complications Consortium(DiaComp) using the following text:
Financial support for this work provided by the NIDDK Diabetic Complications Consortium (RRID:SCR_001415, www.diacomp.org), grants DK076169 and DK115255
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