In the present work, the involvement of JNK in insulin signaling alterations and its role in glutamatergic deficits in Alzheimer’s disease (AD) has been studied. In postmortem cortical tissues, pJNK levels were increased, while insulin signaling and the expression of VGLUT1 were decreased. A significant correlation was found between reduced expression of insulin receptor and VGLUT1. The administration of a JNK inhibitor reversed the decrease in VGLUT1 expression found in a mice model of insulin resistance. It is suggested that activation of JNK in AD inhibits insulin signaling which could lead to a decreased expression of VGLUT1, therefore contributing to the glutamatergic deficit in AD.
SteenE, TerryBM, RiveraEJ, CannonJL, NeelyTR, TavaresR, XuXJ, WandsJR, de la MonteSM (2005) Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease–is this type 3 diabetes?J Alzheimers Dis7, 63–80.
2.
MoloneyAM, GriffinRJ, TimmonsS, O’ConnorR, RavidR, O’NeillC (2010) Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol Aging31, 224–243.
3.
TalbotK, WangHY, KaziH, HanLY, BakshiKP, StuckyA, FuinoRL, KawaguchiKR, SamoyednyAJ, WilsonRS, ArvanitakisZ, SchneiderJA, WolfBA, BennettDA, TrojanowskiJQ, ArnoldSE (2012) Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest122, 1316–1338.
4.
ViswaprakashN, VaithianathanT, ViswaprakashA, JuddR, ParameshwaranK, SuppiramaniamV (2015) Insulin treatment restores glutamate (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor function in the hippocampus of diabetic rats. J Neurosci Res93, 1442–1450.
5.
KirvellSL, ElliottMS, KalariaRN, HortobágyiT, BallardCG, FrancisPT (2010) Vesicular glutamate transporter and cognition in stroke: A case-control autopsy study. Neurology75, 1803–1809.
MudherA, ChapmanS, RichardsonJ, AsuniA, GibbG, PollardC, KillickR, IqbalT, RaymondL, VarndellI, SheppardP, MakoffA, GowerE, SodenPE, LewisP, MurphyM, GoldeTE, RupniakHT, AndertonBH, LovestoneS (2001) Dishevelled regulates the metabolism of amyloid precursor protein via protein kinase C/mitogen-activated protein kinase and c-Jun terminal kinase. J Neurosci21, 4987–4995.
8.
OkazawaH, EstusS (2002) The JNK/c-Jun cascade and Alzheimer’s disease. Am J Alzheimers Dis Other Demen17, 79–88.
9.
Boura-HalfonS, ZickmY (2009) Phosphorylation of IRS proteins, insulin action, and insulin resistance. Am J Physiol Endocrinol Metab296, E581–E591.
10.
SeeburgerJL, HolderDJ, CombrinckM, JoachimC, LaterzaO, TanenM, DallobA, ChappellD, SnyderK, FlynnM, SimonA, ModurV, PotterWZ, WilcockG, SavageMJ, SmithAD (2015) Cerebrospinal fluid biomarkers distinguish postmortem-confirmed Alzheimer’s disease from other dementias and healthy controls in the OPTIMA cohort. J Alzheimers Dis44, 525–539.
11.
SolasM, GerenuG, Gil-BeaFJ, RamírezMJ (2013) Mineralocorticoid receptor activation induces insulin resistance through c-Jun N-terminal kinases in response to chronic corticosterone: Cognitive implications. J Neuroendocrinol25, 350–356.
12.
De FeliceFG (2013) Alzheimer’s disease and insulin resistance: Translating basic science into clinical applications. J Clin Invest123, 531–539
.
13.
SuiL, WangJ, LiBM (2008) Role of the phosphoinositide 3-kinase-Akt-mammalian target of the rapamycin signaling pathway in long-term potentiation and trace fear conditioning memory in rat medial prefrontal cortex. Learn Mem15, 762–776.
14.
LiH, YuX (2013) Emerging role of JNK in insulin resistance. Curr Diabetes Rev9, 422–428.
15.
De la MonteSM (2012) Brain insulin resistance and deficiency as therapeutic targets in Alzheimer’s disease. Curr Alzheimer Res9, 35–66.
16.
YaoJ, RettbergJR, KlosinskiLP, CadenasE, BrintonRD (2011) Shift in brain metabolism in late onset Alzheimer’s disease: Implications for biomarkers and therapeutic interventions. Mol Aspects Med32, 247–257.
17.
JugeN, GrayJA, OmoteH, MiyajiT, InoueT, HaraC, UneyamaH, EdwardsRH, NicollRA, MoriyamaY (2010) Metabolic control of vesicular glutamate transport and release. Neuron68, 99–112.
18.
LiptonSA (2005) The molecular basis of memantine action in Alzheimer’s disease and other neurologic disorders: Low-affinity, uncompetitive antagonism. Curr Alzheimer Res2, 155–165.
