Enhanced Anxiety and Olfactory Microglial Activation in Early-Stage Familial Alzheimer’s Disease Mouse Model

SIMPLE SUMMARY: We observed that compared to wildtype (WT) littermates, 5 × FAD mice showed enhanced anxiety with concomitant increased pro-inflammatory cytokines in the olfactory bulb (OB) but not the frontal cortex (FC) at as early as 2 months old (mo). More prominent microglial activation and morphological changes were also found in the OB of 2 mo 5 × FAD mice. In the FC, pro-inflammatory cytokines were upregulated at the later 5~6 mo stage. Furthermore, myeloid cell number and microglial phagocytosis of presynaptic vesicular glutamate transporter-2 were increased in the OB but not the FC of 5~6 mo 5 × FAD mice. Our findings demonstrated that microglia-mediated neuroinflammation in the OB can be an early-stage biomarker for neuropsychiatric behavior in AD. ABSTRACT: Anxiety is a known comorbidity and risk factor for conversion to neuroinflammation-mediated dementia in patients with Alzheimer’s disease (AD). Here, we investigated if anxiety occurred as an early endophenotype of mutant familial AD (5 × FAD) male mice and the underlying neuroinflammatory mechanisms. We observed that compared to wildtype (WT) littermates, 5 × FAD mice showed enhanced anxiety at as early as 2 months old (mo). Interestingly, these 5 × FAD male mice had concomitantly increased mRNA levels of pro-inflammatory cytokines such as interleukin 1 beta (Il1b) and tumor necrosis factor (Tnf) in the olfactory bulb (OB) but not the frontal cortex (FC). Increased expression of Tnf in the OB was significantly correlated with the anxious behavior in the FAD but not WT mice. Furthermore, we found more prominent microglial activation and morphological changes in the OB of 2 mo 5 × FAD mice, while only microglial ramification was seen in the FC. To understand if neuroinflammatory changes in the FC could occur at a later stage, we studied 5~6 mo male mice and found that Il1b, interleukin 18 (Il18), and Tnf were upregulated in the FC at this older age. Furthermore, we observed that numbers of microglia and macrophage as well as microglial synaptic pruning, as indicated by phagocytosis of presynaptic component of vesicular glutamate transporter-2, were increased in the OB but not the FC of 5~6 mo 5 × FAD mice. Our findings demonstrated the OB as a more sensitive brain region than the cerebral cortex for microglia-mediated neuroinflammation in association with anxiety in FAD mice and supported the notion that the OB can be an early-stage biomarker in AD.