Both insulin resistance (type II diabetes) and β-amyloid (Aβ) oligomers are

Both insulin resistance (type II diabetes) and β-amyloid (Aβ) oligomers are implicated in Alzheimer’s disease (AD). and tau (Ser422) in cultured hippocampal neurons whereas JNK inhibition clogged these reactions. The omega-3 fatty acid docosahexaenoic acid (DHA) similarly inhibited JNK and the phosphorylation of IRS-1 and tau in cultured hippocampal neurons. Feeding 3xTg-AD transgenic mice a diet high in saturated and omega-6 excess fat increased active JNK and phosphorylated IRS-1 and tau. Treatment of the 3xTg-AD mice on high-fat diet with fish oil or curcumin or a combination of both for 4 weeks reduced phosphorylated JNK IRS-1 and tau and prevented the degradation of total IRS-1. This was accompanied by improvement in Y-maze overall performance. Mice fed with fish oil and curcumin for one month experienced more significant effects on Y-maze and the combination showed more significant inhibition of JNK IRS-1 and tau phosphorylation. These data show JNK mediates Aβ oligomer inactivation of IRS-1 and phospho-tau pathology and that diet treatment with fish oil/DHA curcumin or a combination of both has the potential to improve insulin/trophic signaling and cognitive deficits in AD. Intro Alzheimer’s disease (AD) is the most common form of neurodegenerative dementia in the aged. AD is neuropathologically characterized by irregular accumulations of extracellular amyloid plaques and intracellular neurofibrillary tangles throughout cortical and limbic mind areas. Cognitive deficits in AD are widely believed to result from progressive synaptic dysfunction and neurodegeneration initiated by soluble aggregated β-amyloid peptide 1-42 (Aβ42) and further including aggregates of hyperphosphorylated tau a principal component of intracellular neurofibrillary tangles. Epidemiologists find high-fat diet/obesity Rabbit Polyclonal to GJA3. or diabetes that cause insulin resistance are risk factors for AD (Ott et al. 1996 1999 Leibson et al. 1997 In AD mind insulin and insulin signaling are decreased when compared with healthy control subjects (Art et al. 1998 2003 Rivera et al. 2005 Steen et al. 2005 Insulin/insulin receptor (IR) signaling normally takes on a pivotal part in rules of peripheral glucose rate of metabolism and energy homeostasis. In the brain the insulin/IR complex is definitely abundantly distributed in synaptic membranes from the cerebral cortex and hippocampus (Heidenreich et al. 1983 1988 Rhoads and Matsumoto 1990 Zhao et al. 1999 and features to modify synaptic actions that are necessary for learning and storage (Hendricks et al. 1984 Lowe et al. 1986 Biessels et al. 1996 Wan et al. 1997 Zhao and Alkon 2001 In β-amyloid precursor (APP) transgenic (Tg2576) Advertisement model mice Imperatorin insulin level of resistance develops recommending some hyperlink between Aβ and insulin signaling (Pedersen and Flynn 2004 Trophic aspect or insulin receptors are Imperatorin tyrosine kinases which autophosphorylate after activation by ligands leading to reputation by insulin receptor substrate (IRS-1 and IRS-2) adaptors (Light 2002 IRS is certainly after that phosphorylated at tyrosines permitting recruitment of SH2 (Src Imperatorin homology 2)-domain-containing protein including phosphatidylinositol (PI) 3-kinase (Sunlight et al. 1995 This activates signaling pathways in charge of the pleiotropic activities of insulin (Virkam?ki et al. 1999 With insulin level of resistance in diabetics and versions IRS-1 is certainly phosphorylated at Ser312 by insulin-stimulated or stress-activated kinases including c-Jun N-terminal kinase (JNK) which uncouples IRS-1 (Aguirre et al. 2002 and sets off fast IRS-1 degradation (Sunlight et al. 1999 yielding a lacking sign transduction response (Pederson et al. 2001 Rui et al. 2001 IRS deficits donate to insulin level of resistance in animal versions and diabetics (Saad et al. 1992 Rondinone et al. 1997 Considerably decreased IRS-1 and IRS-2 take place in Advertisement brain followed by raised cytosolic phospho-IRS-1 (Ser312 and Ser616). These phosphoserine epitopes colocalize with neurofibrillary tangles recommending a possible hyperlink between “insulin level of resistance” and tau pathology (Moloney et al. 2008 IRS-1 is certainly phosphorylated at different serine/threonine residues by multiple kinases including JNK1 (Aguirre Imperatorin et al. 2000 Lee et al. 2003 Rho kinase (Begum et al. 2002 proteins kinase Cζ (PKCζ) (Liu et al. 2001 PI3-K/Akt/mTOR (mammalian focus on of rapamycin) (Ozes et al. 2001 and inhibitor κB kinase (Gao et al. 2002 but JNK Imperatorin is certainly many implicated in Advertisement. Activated JNK is certainly induced by reactive air types (Shen and Liu.