An Investigation of the Inflammatory Landscape in the Brain and Bone Marrow of the APP/PS1 Mouse.

Abstract

Background: The APP/PS1 mouse model recapitulates pathology of human Alzheimer's disease (AD). While amyloid-β peptide deposition and neurodegeneration are features of AD, the pathology may involve inflammation and impaired vascular regeneration.

Objective: This study evaluated inflammatory environments in the brain and bone marrow (BM), and the impact on brain microvascular density.

Methods: BM and frontal cortex from male nine-month-old APP/PS1 or the control C57Bl6/j mice were studied. Vascular density and inflammatory cells were evaluated in the sections of frontal cortex by immunohistochemistry. Different subsets of hematopoietic stem/progenitor cells (BM) and monocyte-macrophages were characterized by flow cytometry and by clonogenic assays. Myelopoietic or inflammatory factors were evaluated by real-time RT-PCR or by western blotting.

Results: CD34⁺ or CD31⁺ vascular structures were lower (p < 0.01, n = 6) in the frontal cortex that was associated with decreased number of Lin^-Sca-1⁺cKit⁺ vasculogenic progenitor cells in the BM and circulation (p < 0.02, n = 6) compared to the control. Multipotent progenitor cells MPP4, common lymphoid, common myeloid and myeloid progenitor cells were higher in the APP/PS1-BM compared to the control, which agreed with increased numbers of monocytes and pro-inflammatory macrophages. The expression of pro-myelopoietic factors and alarmins was higher in the APP/PS1 BM-HSPCs or in the BM-supernatants compared to the control. Frontal cortices of APP/PS1 mice showed higher number of pro-inflammatory macrophages (CD11b⁺F4/80⁺ or CD80⁺) and microglia (OX42⁺Iba1⁺).

Conclusions: These findings show that AD pathology in APP/PS1 mice is associated with upregulated myelopoiesis, which contributes to the brain inflammation and decreased vascularity.