Upregulated expression of a subset of genes in APP;ob/ob mice: Evidence of an interaction between diabetes‐linked obesity and Alzheimer’s disease

• Main Authors: Mitsuru Shinohara, Masataka Kikuchi, Miyuki Onishi‐Takeya, Yoshitaka Tashiro, Kaoru Suzuki, Yasuhiro Noda, Shuko Takeda, Masahiro Mukouzono, Seiichi Nagano, Akio Fukumori, Ryuichi Morishita, Akihiro Nakaya, Naoyuki Sato
• Format: Article
• Language: English
• Published: Wiley 2021-05-01
• Series: FASEB BioAdvances
• Subjects: Alzheimer's disease; animal models; diabetes; interaction; obesity
• Online Access: https://doi.org/10.1096/fba.2020-00151

Abstract Clinical studies have indicated that obesity and diabetes are associated with Alzheimer's disease (AD) and neurodegeneration. However, the mechanism by which obesity/diabetes and AD interact with each other and contribute to dementia remains elusive. To obtain insights into their interaction at molecular levels, we performed gene expression analysis of APP;ob/ob mice, which were generated by crossing transgenic AD model mice (APP23 mice) with ob/ob mice, which are obese and mildly diabetic. The Aβ level in these mice was reduced compared with that in pure APP mice. However, we identified a cluster of genes (cluster 10) upregulated in APP;ob/ob mice but not in either APP or ob/ob mice. Interestingly, genes upregulated in the human AD brain were enriched in cluster 10. Moreover, genes in cluster 10 formed a network and shared upregulated genes with a cell model of neurodegeneration and other models of neurological disorders such as ischemia and epilepsy. In silico analyses showed that serum response factor (SRF), recently identified in a single‐cell analysis of human brains as a transcription factor that can control the conversion from healthy cells to AD cells, might be a common transcriptional regulator for a subset of cluster 10 genes. These data suggest that upregulation of genes uniquely associated with APP;ob/ob mice is an evidence of the interaction between obesity/diabetes and AD.