title: Neuroinflammation is not a Prerequisite for Diabetes-induced Tau Phosphorylation.
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.
authors.affiliation: Department of Genome Analysis, Academic Medical Center, University of Amsterdam Amsterdam, Netherlands ; Departments of Functional Genomics and Molecular and Cellular Neuroscience, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam Amsterdam, Netherlands.
authors.forename: Judith M
authors.initials: JM
authors.lastname: van der Harg
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam Amsterdam, Netherlands.
authors.forename: Leslie
authors.initials: L
authors.lastname: Eggels
authors.affiliation: Departments of Functional Genomics and Molecular and Cellular Neuroscience, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam Amsterdam, Netherlands.
authors.forename: Silvie R
authors.initials: SR
authors.lastname: Ruigrok
authors.affiliation: Department of Pathology, Neuroscience Campus Amsterdam, VU University Medical Center Amsterdam, Netherlands.
authors.forename: Jeroen J M
authors.initials: JJ
authors.lastname: Hoozemans
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam Amsterdam, Netherlands.
authors.forename: Susanne E
authors.initials: SE
authors.lastname: la Fleur
authors.affiliation: Department of Genome Analysis, Academic Medical Center, University of Amsterdam Amsterdam, Netherlands ; Departments of Functional Genomics and Molecular and Cellular Neuroscience, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam Amsterdam, Netherlands ; Department of Clinical Genetics and Alzheimer Center, VU University Medical Center Amsterdam, Netherlands.
authors.forename: Wiep
authors.initials: W
authors.lastname: Scheper
keywords: Alzheimer's disease; Diabetes Mellitus; cortex; hippocampus; neuroinflammation; phosphorylated tau