Marc L Goalstone1. 1. Department of Medicine, University of Colorado Denver and the Research Section of Eastern Colorado Healthcare Service, Denver, Colorado, USA.
Abstract
BACKGROUND: Alzheimer's Disease (AD) is characterized in part by the increased presence of neurofibrillary tangles and amyloid beta (Aβ) plaques. Alzheimer's Disease is considered an inflammatory disease and, as such, nuclear factor-kappaB (NFκB) plays an important role in the pathophysiology of AD. Insulin acts as a neurotrophic factor. Yet, in the context of insulin resistance, concomitant hyperinsulinemia may contribute to the pathogenesis of AD. METHODS: Rat Primmary Hippocampal Neurons (RPHN) were treated with insulin in the absence and presence of Wortmannin and ERK5 small inhibitory RNA and assayed for downstream effectors of activated ERK5. RESULTS: Here we demonstrate that genetic inhibition of ERK5 blocks insulin stimulated (1) activation and translocation of ERK5 and NFκB, (2) phosphorylation of IKKα via association with ERK5, (3) increases in Aβ1-40 and Aβ1-42 soluble proteins 3-fold and 2.2-fold, respectively, and (4) increases in tau phosphorylation in RPHN. CONCLUSIONS: ERK5 plays an active role in insulin signaling in neurons and may be a potential therapeutic target for neurodegenerative diseases.
BACKGROUND:Alzheimer's Disease (AD) is characterized in part by the increased presence of neurofibrillary tangles and amyloid beta (Aβ) plaques. Alzheimer's Disease is considered an inflammatory disease and, as such, nuclear factor-kappaB (NFκB) plays an important role in the pathophysiology of AD. Insulin acts as a neurotrophic factor. Yet, in the context of insulin resistance, concomitant hyperinsulinemia may contribute to the pathogenesis of AD. METHODS:Rat Primmary Hippocampal Neurons (RPHN) were treated with insulin in the absence and presence of Wortmannin and ERK5 small inhibitory RNA and assayed for downstream effectors of activated ERK5. RESULTS: Here we demonstrate that genetic inhibition of ERK5 blocks insulin stimulated (1) activation and translocation of ERK5 and NFκB, (2) phosphorylation of IKKα via association with ERK5, (3) increases in Aβ1-40 and Aβ1-42 soluble proteins 3-fold and 2.2-fold, respectively, and (4) increases in tau phosphorylation in RPHN. CONCLUSIONS:ERK5 plays an active role in insulin signaling in neurons and may be a potential therapeutic target for neurodegenerative diseases.
Authors: A E S Simões; D M Pereira; S E Gomes; H Brito; T Carvalho; A French; R E Castro; C J Steer; S N Thibodeau; C M P Rodrigues; P M Borralho Journal: Cell Death Dis Date: 2015-04-09 Impact factor: 8.469