Systems biologic analysis of inverse etiological mechanism between Alzheimer’s disease and cancer identified key astrocytic signaling pathways in restraining Alzheimer’s disease pathogenesis

Abstract

AbstractBackgroundA 35% lower incidence of Alzheimer’s disease (AD) among older cancer survivors was reported versus those without cancer history(Ma, Yu et al. 2014, Zhang, Guo et al. 2015, Bowles, Walker et al. 2017, Ospina‐Romero, Abdiwahab et al. 2019, Ospina‐Romero, Glymour et al. 2020). The exclusive cellular and molecular mechanism between these two diseases may open up new vista in discovering novel mechanisms of action and effective therapeutic strategies for AD.MethodA breast cancer‐in‐AD mouse model was established by injecting a very low number of AT3 murine breast cancer cells (1×104) into the left cardiac ventricle of 1‐month‐old female 5xFAD mice (Tg6799 on a congenic C57BL6 background, n = 5). Mice were sacrificed four weeks after tumor injection. Their brains were processed for amyloid plaque, astrocyte, microglia and oligodendrocyte immunostaining and isolation of astrocytes and microglia for generating cell‐specific RNA sequencing data, which were analyzed and then modeled by the CCCExplorer software(Choi, Sheng et al. 2015, Tsz‐Lun Yeung 2019) to identify multi‐cellular crosstalk signaling in association with plaque burden.ResultIn the breast cancer‐in‐AD mouse model, we identified a significant reduction (45%) of Aβ plaque burden in the brain of tumor‐bearing AD mice in comparing to the age‐matched cancer‐free AD mice (Fig. 1). We observed an 35% increase of the total astrocyte area and 50% increase of plaque‐associated astrocytes in the tumor‐bearing AD mice (Fig. 2). Our systems biologic analysis indicated the elevated expressions of about 50 marker genes for reactive astrocytes and positive regulators of astrocyte reactivity; suppression of Aβ production but increase of Aβ clearance in astrocytes of tumor‐bearing AD mice, and identification of 1,729 differentially expressed genes (DEGs) including 46 receptors, 45 ligands, and 12 signaling pathways of astrocytes in mediating an active astrocyte‐microglia interaction in synergistically regulating Aβ homeostasis (Fig. 3).ConclusionAmyloid burden is significantly reduced in AD mice bearing tumors, predominantly associated with astrocyte activation. The AD protective astrocyte signaling is being investigated for repositioning known drugs targeting early AD.