Marciniak E, Leboucher A, Caron E, Ahmed T, Tailleux A, Dumont J, Issad T, Gerhardt E, Pagesy P, Vileno M, Bournonville C, Hamdane M, Bantubungi K, Lancel S, Demeyer D, Eddarkaoui S, Vallez E, Vieau D, Humez S, Faivre E, Grenier-Boley B, Outeiro TF, Staels B, Amouyel P, Balschun D, Buee L, Blum D. Tau deletion promotes brain insulin resistance. J Exp Med. 2017 Aug 7;214(8):2257-2269. Epub 2017 Jun 26 PubMed.
Recommends
Please login to recommend the paper.
Comments
Federal University of Rio de Janeiro
This is an interesting report by Elodie Marciniak, Luc Buee, David Blum, and colleagues providing evidence that tau is necessary for proper brain insulin signaling. Results are significant, as they highlight an as-yet-unexplored physiological role of tau, as well as lead us to speculate whether brain insulin resistance could contribute to tauopathies.
Several reports have now demonstrated that insulin-induced responses are blunted in Alzheimer's disease brains (Ma et al., 2009; Moloney et al., 2010; Bomfim et al., 2012; Talbot et al., 2012). The current report opens new fields of investigation by implicating tau as a key regulator of brain insulin signaling through PTEN phosphatase regulation. It would be important to determine next whether mouse models of tauopathies present brain insulin resistance, and whether it depends on tau phosphorylation, cleavage, or aggregation.
Downregulation of brain insulin receptors was shown to trigger memory impairment (Nisticò et al., 2010; Grillo et al., 2015) and tau phosphorylation (Schubert et al., 2004). Although tau regulation of insulin signaling does not appear to directly involve insulin receptors, defective brain insulin signaling could be part of a feed-forward loop driving neuronal malfunction in tauopathies, as now suggested
Finally, the findings that tau regulates non-hippocampal metabolic actions of insulin in the brain is in line with recent evidence underscoring disturbances of peripheral metabolism in AD (Clarke et al., 2015; Crane et al., 2015). Further investigation of tau and insulin intersections would thus indicate whether stimulating brain insulin signaling through repurposed anti-diabetic agents holds potential to attenuate cognitive and metabolic symptoms of tauopathies, as currently under investigation in the AD field.
References:
Bomfim TR, Forny-Germano L, Sathler LB, Brito-Moreira J, Houzel JC, Decker H, Silverman MA, Kazi H, Melo HM, McClean PL, Holscher C, Arnold SE, Talbot K, Klein WL, Munoz DP, Ferreira ST, De Felice FG. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers. J Clin Invest. 2012 Apr 2;122(4):1339-53. PubMed.
Clarke JR, Lyra E Silva NM, Figueiredo CP, Frozza RL, Ledo JH, Beckman D, Katashima CK, Razolli D, Carvalho BM, Frazão R, Silveira MA, Ribeiro FC, Bomfim TR, Neves FS, Klein WL, Medeiros R, LaFerla FM, Carvalheira JB, Saad MJ, Munoz DP, Velloso LA, Ferreira ST, De Felice FG. Alzheimer-associated Aβ oligomers impact the central nervous system to induce peripheral metabolic deregulation. EMBO Mol Med. 2015 Jan 23;7(2):190-210. PubMed.
Crane PK, Walker R, Larson EB. Glucose levels and risk of dementia. N Engl J Med. 2013 Nov 7;369(19):1863-4. PubMed.
Grillo CA, Piroli GG, Lawrence RC, Wrighten SA, Green AJ, Wilson SP, Sakai RR, Kelly SJ, Wilson MA, Mott DD, Reagan LP. Hippocampal Insulin Resistance Impairs Spatial Learning and Synaptic Plasticity. Diabetes. 2015 Nov;64(11):3927-36. Epub 2015 Jul 27 PubMed.
Ma QL, Yang F, Rosario ER, Ubeda OJ, Beech W, Gant DJ, Chen PP, Hudspeth B, Chen C, Zhao Y, Vinters HV, Frautschy SA, Cole GM. Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. J Neurosci. 2009 Jul 15;29(28):9078-89. PubMed.
Moloney AM, Griffin RJ, Timmons S, O'Connor R, Ravid R, O'Neill C. 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 Aging. 2010 Feb;31(2):224-43. PubMed.
Nisticò R, Cavallucci V, Piccinin S, Macrì S, Pignatelli M, Mehdawy B, Blandini F, Laviola G, Lauro D, Mercuri NB, D'Amelio M. Insulin Receptor β-Subunit Haploinsufficiency Impairs Hippocampal Late-Phase LTP and Recognition Memory. Neuromolecular Med. 2012 Jun 3; PubMed.
Schubert M, Gautam D, Surjo D, Ueki K, Baudler S, Schubert D, Kondo T, Alber J, Galldiks N, Küstermann E, Arndt S, Jacobs AH, Krone W, Kahn CR, Brüning JC. Role for neuronal insulin resistance in neurodegenerative diseases. Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3100-5. PubMed.
Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, Fuino RL, Kawaguchi KR, Samoyedny AJ, Wilson RS, Arvanitakis Z, Schneider JA, Wolf BA, Bennett DA, Trojanowski JQ, Arnold SE. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. 2012 Apr;122(4):1316-38. PubMed.
View all comments by Mychael LourencoMake a Comment
To make a comment you must login or register.