Brain "Metaflammasome" and risk factors associated with Alzheimer's disease

Abstract

A number of environmental and genetic risk factors have been identified for Alzheimer’s disease (AD) in addition to the well-known factors of ageing and APOE gene polymorphism. These include mainly lipid metabolism (e.g.diabetes) and inflammation. Recent evidence in models of the metabolic disorders obesity and type 2 diabetes suggest the involvement of a metabolic inflammasome (“metaflammasome”) in mediating chronic inflammation. The central component of the metaflammasome is the double-stranded RNA-dependent protein kinase (PKR), which also accumulates in AD brains. Other components of the metaflammasome include the proteins JNK, IKK?and IRS1. Chronic neuroinflammation is a key feature of AD. Therefore my hypothesis is that metabolic risk factors for AD activate a cerebral metaflammasome which, in turn, results in inflammation. To test my hypothesis, I investigated the expression of cerebral metaflammasome components in animals and humans. The effect of the absence of PKR on other metaflammasome components was studied using PKR-/- mice. In an acute model of systemic inflammation, using western blots and immunohistochemistry (IHC) methods, my study showed the absence of the expression of a cerebral metaflammasome in Wild-Type (WT) (n=8) and PKR-/- mice (n=3) at day 1. Similar results were obtained at day 3 (n=3 for both strains) by IHC. However, the results of our chronic high fat diet model (HFD), to reproduce obesity, showed in the WT obese mice (n=14), which developed type 2 diabetes and dyslipidaemia, increased expression of cerebral metaflammasome proteins compared to WT control mice (n=12). Interestingly, no significant difference in the expression of the metaflammasome was observed in PKR-/- HFD mice (n=5) compared to controls (n=4), supporting a key role for PKR in the metaflammasome. Furthermore, no development of type 2 diabetes and dyslipidaemia was found in PKR-/- HFD mice unlike in WT HFD mice. The inhibition of PKR and metaflammasome components could protect against metabolic disorders, which are known risk factors for AD.In the human study, analysis obtained by IHC on brain tissue from 298 participants in the Cognitive Function and Ageing Studies (CFAS) showed that high levels of PKR, JNK and IRS1 were significantly associated with poor cognitive function while a high level of IKK? was associated with good cognitive function (p&lt;0.05). Among participants without dementia, an increase in metaflammasome proteins was related to a lower neuropathological burden such as plaques and tangles. In contrast, among those with AD, higher levels of metaflammasome proteins were mainly associated with more severe AD pathology (p&lt;0.05). Metaflammasome proteins were positively related to hypertension in non-demented participants, but negatively in those with AD (p&lt;0.05). Regarding diabetes, metaflammasome proteins were negatively associated in both groups, except for JNK (p&lt;0.05). Interestingly, in the presence of dementia, a novel relationship was observed between JNK and IKK?. APOE genotype did not affect metaflammasome proteins. In these studies, we have demonstrated for the first time the presence of a cerebral metaflammasome in the context of metabolic disorders in animals and humans. The animal data suggest an association of the cerebral metaflammasome with metabolic disorders and support the central function of PKR in the expression of metaflammasome components. The human data show an association between the metaflammasome and metabolic disorders, cognitive function and AD pathology, and highlight the modification of relationship between JNK and IKK? during dementia.<br/