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Metaflammasome components in the human brain: a role in dementia with Alzheimer’s pathology?

Metaflammasome components in the human brain: a role in dementia with Alzheimer’s pathology?
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 IKK? (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 IKK? [pSer176/180], IRS1 [pS312], JNK [pThr183/Tyr185] and PKR [pT451]. The data were analysed 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 IKK? 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 IKK? and IRS1. Cognitive scores showed a significant positive relationship with IKK? 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.
1-25
Taga, Mariko
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Minett, Thais
57b495a8-8be2-4757-a3c9-413acbb60b80
Classey, John
193d01fb-df0b-4b0a-a098-5fd6a59c3e7a
Matthews, Fiona
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Brayne, Carol
978cfad1-c7f6-4f79-aa1c-4f189eaaf035
Ince, Paul
bf15554a-8c61-4aae-ad9e-75127d6d21ea
Nicoll, James
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Hugon, Jacques
de69c379-343f-42c5-ac70-0fb19eefd0bb
Boche, Delphine
bdcca10e-6302-4dd0-919f-67218f7e0d61
Taga, Mariko
7d141f5d-087a-4439-8148-4f99307bc6e4
Minett, Thais
57b495a8-8be2-4757-a3c9-413acbb60b80
Classey, John
193d01fb-df0b-4b0a-a098-5fd6a59c3e7a
Matthews, Fiona
c0f3cef0-85d9-4b1b-8a1b-95dbe29e53b7
Brayne, Carol
978cfad1-c7f6-4f79-aa1c-4f189eaaf035
Ince, Paul
bf15554a-8c61-4aae-ad9e-75127d6d21ea
Nicoll, James
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Hugon, Jacques
de69c379-343f-42c5-ac70-0fb19eefd0bb
Boche, Delphine
bdcca10e-6302-4dd0-919f-67218f7e0d61

Taga, Mariko, Minett, Thais and Classey, John et al. (2016) Metaflammasome components in the human brain: a role in dementia with Alzheimer’s pathology? Brain Pathology, 1-25. (doi:10.1111/bpa.12388). (PMID:27106634)

Record type: Article

Abstract

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 IKK? (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 IKK? [pSer176/180], IRS1 [pS312], JNK [pThr183/Tyr185] and PKR [pT451]. The data were analysed 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 IKK? 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 IKK? and IRS1. Cognitive scores showed a significant positive relationship with IKK? 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.

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More information

Accepted/In Press date: 19 April 2016
e-pub ahead of print date: 22 April 2016
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 393170
URI: https://eprints.soton.ac.uk/id/eprint/393170
PURE UUID: 2d13f330-8ca3-405b-9a97-4a86d8a9b1cc
ORCID for James Nicoll: ORCID iD orcid.org/0000-0002-9444-7246
ORCID for Delphine Boche: ORCID iD orcid.org/0000-0002-5884-130X

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Date deposited: 22 Apr 2016 09:21
Last modified: 10 Dec 2019 06:34

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