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P3‐028: Mechanistic pathways linking mitochondrial oxidative stress and white matter degeneration in the aging mammalian female brain
Author(s) -
Klosinski Lauren,
Yao Jia,
Chen Shuhua,
Mao Jennifer,
Trushina Eugenia,
Tiwari-Woodruff Seema,
Diaz-Brinton Roberta
Publication year - 2015
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2015.06.894
Subject(s) - myelin , biology , sphingomyelin , oxidative stress , ceramide , endocrinology , white matter , medicine , catabolism , biochemistry , microbiology and biotechnology , central nervous system , metabolism , apoptosis , radiology , cholesterol , magnetic resonance imaging
chronic inflammation. In addition, the GWAS studies have identified genes involved in lipid metabolism and inflammation as risk factors for AD. Recent evidences in obesity and diabetes suggest that the metabolic inflammasome (“metaflammasome”) mediates chronic inflammation. The neurodegenerative marker doublestranded RNA-dependent protein kinase (PKR), accumulates in AD brains and is a central component of the metaflammasome. We hypothesize that obesity can activate a cerebral metaflammasome causing neuroinflammation and that is partially controlled by PKR. Methods: Expression of the phosphorylated components of the metaflammasome, pPKR, pJNK, pIRS1 and pIKKb, as well as the microglial marker Iba1 have been studied in the brains of wild-type (WT) and knock out PKR (PKR) mice fed with a high fat diet (HFD) for 16 weeks. WT and PKRmice fed with a normal diet were used as controls. Results: Western blot and immunohistochemistry results showed a significant increase (p<0.05) of pPKR, pJNK, and pIRS1 in the cortex of WT HFD mice. A trend towards an increase of pIKKb was also observed in the cortex of WT HFD mice. However, no significant difference of metaflammasome protein expression was observed in PKR HFD mice compared to HFD controls. Furthermore, no development of type 2 diabetes and dyslipidaemia was found in PKRHFD mice as observed in WT HFD mice. Conclusions:We showed that the induction of a general chronic lipid stress with metabolic syndrome is associated with an increased expression of cerebral metaflammasome proteins and that genetic down-regulation of PKR, a central component of the metaflammasome, prevented the development of a type 2 diabetes and dyslipidaemia. Thus the inhibition of PKR and metaflammasome components could be a new pharmacological target aimed at initiating protection against metabolic disorders and neuroinflammation, known as the risk factors for AD.