Endoplasmic reticulum stress contributes to the decline in doublecortin expression in the immature neurons of mice with long-term obesity

Kiyomi Nakagawa,Masashi Ueda,Toshiyuki Nakagawa,Saiful Islam

doi:10.1038/s41598-022-05012-5

Abstract

Adult hippocampal neurogenesis (AHN) plays an important role in hippocampus-dependent function. The number of doublecortin (Dcx)-positive immature neurons in the dentate gyrus decreases over time, especially in the early stages of Alzheimer’s disease (AD), and is further reduced in later stages of AD. Obesity in midlife is associated with dementia later in life; however, the underlying mechanisms by which obesity results in the development of dementia later in life remain unknown. Here, we show that endoplasmic reticulum (ER) stress was activated in the hippocampus and processes of Dcx-expressing immature neurons were shortened, coexpressing CHOP in APP23 AD model mice with high-fat diet-induced long-term obesity and in aged Leprdb/db (db/db) mice. Moreover, in cells differentiating from hippocampal neurospheres, Dcx mRNA was rapidly degraded via a microRNA (miRNA) pathway after thapsigargin treatment in vitro. These results indicate that loss of Dcx mRNA induced by ER stress during AHN may cause memory impairment in obese individuals later in life.

Highlights

Adult hippocampal neurogenesis (AHN) plays an important role in hippocampus-dependent function
We demonstrated that long-term obesity induced endoplasmic reticulum (ER) stress, mainly via the activating transcription factor 4 (ATF4)-C/ EBP-homologous protein (CHOP) axis, in the hippocampal dentate gyrus (DG), leading to a decrease in the number of processes on Dcx-expressing immature neurons due to the loss of Dcx mRNA stability
The ATF4-CHOP axis is initiated by ER-localized translation initiation factor 2α (eIF2α) phosphorylation, which is mediated by four protein kinases, through a process called the integrated stress response (ISR), which contributes to the pathogenesis of diseases, including cognitive disorders[29]

Summary

Introduction

Adult hippocampal neurogenesis (AHN) plays an important role in hippocampus-dependent function. We show that endoplasmic reticulum (ER) stress was activated in the hippocampus and processes of Dcx-expressing immature neurons were shortened, coexpressing CHOP in APP23 AD model mice with high-fat diet-induced long-term obesity and in aged Leprdb/db (db/db) mice. In cells differentiating from hippocampal neurospheres, Dcx mRNA was rapidly degraded via a microRNA (miRNA) pathway after thapsigargin treatment in vitro These results indicate that loss of Dcx mRNA induced by ER stress during AHN may cause memory impairment in obese individuals later in life. The number of cells positive for doublecortin (Dcx), which is expressed in immature neurons, in the DG is decreased in patients with mild cognitive impairment (MCI)[9] and those in the early stages. Downregulation of ATF4 expression by quercetin in mouse models of AD improves memory impairment[19]

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Conclusion