Abstract
Abnormal phosphorylation and aggregation of tau is a key hallmark of Alzheimer's disease (AD). AD is a multifactorial neurodegenerative disorder for which Diabetes Mellitus (DM) is a risk factor. In animal models for DM, the phosphorylation and aggregation of tau is induced or exacerbated, however the underlying mechanism is unknown. In addition to the metabolic dysfunction, DM is characterized by chronic low-grade inflammation. This was reported to be associated with a neuroinflammatory response in the hypothalamus of DM animal models. Neuroinflammation is also implicated in the development and progression of AD. It is unknown whether DM also induces neuroinflammation in brain areas affected in AD, the cortex and hippocampus. Here we investigated whether neuroinflammation could be the mechanistic trigger to induce tau phosphorylation in the brain of DM animals. Two distinct diabetic animal models were used; rats on free-choice high-fat high-sugar (fcHFHS) diet that are insulin resistant and streptozotocin-treated rats that are insulin deficient. The streptozotocin-treated animals demonstrated increased tau phosphorylation in the brain as expected, whereas the fcHFHS diet fed animals did not. Remarkably, neither of the diabetic animal models showed reactive microglia or increased GFAP and COX-2 levels in the cortex or hippocampus. From this, we conclude: 1. DM does not induce neuroinflammation in brain regions affected in AD, and 2. Neuroinflammation is not a prerequisite for tau phosphorylation. Neuroinflammation is therefore not the mechanism that explains the close connection between DM and AD.
Highlights
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by aggregation of Aβ and abnormal phosphorylation and aggregation of tau (Grundke-Iqbal et al, 1986; Selkoe, 1991)
To ascertain that tau phosphorylation did not occur as an adaptive response just after the start of the free-choice high-fat high-sugar (fcHFHS) diet that disappeared after adjustment to the diet, tau phosphorylation was studied at earlier time points
Western blot analyses of tau phosphorylation at Ser396 were performed in STZ-treated rats showing increased levels of phosphorylated tau in the STZ model using this method as well (Supplementary Figure 1). These results demonstrate that -in contrast to the STZ model- the fcHFHS diet model does not induce tau phosphorylation
Summary
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by aggregation of Aβ and abnormal phosphorylation and aggregation of tau (Grundke-Iqbal et al, 1986; Selkoe, 1991). Neuroinflammation is associated with the development and progression of AD. Different genome-wide association studies identified genes involved in the innate immune system as risk factors for AD; CR1, CD33, and TREM2, which are all expressed in microglia. Frontiers in Neuroscience | www.frontiersin.org van der Harg et al. Neuroinflammation not related to tau (Bertram et al, 2008; Harold et al, 2009; Lambert et al, 2009; Jonsson et al, 2013). The density of activated microglial correlates inversely with cognitive performance of AD patients (Combs, 2009). These data strongly indicate the involvement of neuroinflammation in AD pathogenesis
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