Metaflammasome components in the human brain: a role in dementia with Alzheimer's pathology?
Epidemiological and genetic studies have identified metabolic disorders and inflammation as risk factors for Alzheimer's disease (AD). Evidence in obesity and type-2 diabetes suggests a role for a metabolic inflammasome ("metaflammasome") in mediating chronic inflammation in peripheral organs implicating IKKβ (inhibitor of nuclear factor kappa-B kinase subunit beta), IRS1 (insulin receptor substrate 1), JNK (c-jun N-terminal kinase), and PKR (double-stranded RNA protein kinase). We hypothesized that these proteins are expressed in the brain in response to metabolic risk factors in AD. Neocortex from 299 participants from the MRC Cognitive Function and Ageing Studies was analysed by immunohistochemistry for the expression of the phosphorylated (active) form of IKKβ [pSer176/180], IRS1 [pS312], JNK [pThr183/Tyr185] and PKR [pT451]. The data were analyzed to investigate whether the proteins were expressed together and in relation with metabolic disorders, dementia, Alzheimer's pathology and APOE genotype. We observed a change from a positive to a negative association between the proteins and hypertension according to the dementia status. Type-2 diabetes was negatively related with the proteins among participants without dementia; whereas participants with dementia and AD pathology showed a positive association with JNK. A significant association between IKKβ and JNK in participants with dementia and AD pathology was observed, but not in those without dementia. Otherwise, weak to moderate associations were observed among the protein loads. The presence of dementia was significantly associated with JNK and negatively associated with IKKβ and IRS1. Cognitive scores showed a significant positive relationship with IKKβ and a negative with IRS1, JNK and PKR. The proteins were significantly associated with pathology in Alzheimer's participants with the relationship being inverse or not significant in participants without dementia. Expression of the proteins was not related to APOE genotype. These findings highlight a role for these proteins in AD pathophysiology but not necessarily as a complex.
Clinical Neurosciences, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.|INSERM U942, Paris, France.
Mariko
M
Taga
Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK.|Department of Radiology, University of Cambridge, Cambridge, UK.
Thais
T
Minett
Clinical Neurosciences, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
John
J
Classey
MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, UK.
Fiona E
FE
Matthews
Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK.
Carol
C
Brayne
Department of Neuroscience, Sheffield Institute for Translational Neuroscience, Sheffield University, Sheffield, UK.
Paul G
PG
Ince
Clinical Neurosciences, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.|Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
James Ar
JA
Nicoll
INSERM U942, Paris, France.|University of Paris Diderot, Sorbonne Paris Cité, Paris, France.|Centre Memoire de Ressources et de Recherche Paris Nord Ile de France AP-HP, Hôpital Lariboisière, Paris, France.
Jacques
J
Hugon
Clinical Neurosciences, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
Delphine
D
Boche
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D001057:Apolipoproteins E / Q000235:genetics; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007150:Immunohistochemistry; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008297:Male; D008609:Mental Status Schedule; D019579:Neocortex / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D011110:Polymorphism, Genetic; D012307:Risk Factors; D019892:eIF-2 Kinase / Q000378:metabolism*
D001057:Apolipoproteins E; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C000602769:EIF2AK2 protein, human; D019892:eIF-2 Kinase; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; D048670:MAP Kinase Kinase 4
Alzheimer's disease; CFAS; dementia; human brain; metaflammasome