Andrographolide promotes hippocampal neurogenesis and spatial memory in the APPswe/PS1\u0394E9 mouse model of Alzheimer\u2019s disease

Sebastian B Arredondo,Lorena Varela-Nallar,Daniel T Reyes,Nibaldo C Inestrosa,Andrea Herrera-Soto,Muriel D Mardones

doi:10.1038/s41598-021-01977-x

Abstract

In Alzheimer´s disease (AD) there is a reduction in hippocampal neurogenesis that has been associated to cognitive deficits. Previously we showed that Andrographolide (ANDRO), the main bioactive component of Andrographis paniculate, induces proliferation in the hippocampus of the APPswe/PSEN1ΔE9 (APP/PS1) mouse model of AD as assessed by staining with the mitotic marker Ki67. Here, we further characterized the effect of ANDRO on hippocampal neurogenesis in APP/PS1 mice and evaluated the contribution of this process to the cognitive effect of ANDRO. Treatment of 8-month-old APP/PS1 mice with ANDRO for 4 weeks increased proliferation in the dentate gyrus as evaluated by BrdU incorporation. Although ANDRO had no effect on neuronal differentiation of newborn cells, it strongly increased neural progenitors, neuroblasts and newborn immature neurons, cell populations that were decreased in APP/PS1 mice compared to age-matched wild-type mice. ANDRO had no effect on migration or in total dendritic length, arborization and orientation of immature neurons, suggesting no effects on early morphological development of newborn neurons. Finally, ANDRO treatment improved the performance of APP/PS1 mice in the object location memory task. This effect was not completely prevented by co-treatment with the anti-mitotic drug TMZ, suggesting that other effects of ANDRO in addition to the increase in neurogenesis might underlie the observed cognitive improvement. Altogether, our data indicate that in APP/PS1 mice ANDRO stimulates neurogenesis in the hippocampus by inducing proliferation of neural precursor cells and improves spatial memory performance.

Highlights

Alzheimer’s disease (AD) is the most common cause of dementia with an estimated prevalence of 30 million people worldwide[1]
A significant decrease in cells positive for Ki67 was observed in the dentate gyrus of APPswe/PSEN1ΔE9 mice compared to non-transgenic littermates (Fig. 1B), and as we previously reported[24], an increase in Ki67-positive cells was observed in APPswe/ PSEN1ΔE9 mice treated with ANDRO (Fig. 1B)
We reported that ANDRO treatment for 4 weeks increased the number of cells positive for the mitotic marker Ki67, which was demonstrated in the present study, and increased DCX staining in the hippocampus of the APPswe/PSEN1ΔE9 mouse model of AD24

Summary

Introduction

Alzheimer’s disease (AD) is the most common cause of dementia with an estimated prevalence of 30 million people worldwide[1]. Adult-born neurons contribute to hippocampal p lasticity[16,17,18,19] and hippocampaldependent tasks such as pattern separation, cognitive flexibility, and spatial learning and memory[20,21,22]. In humans, it was suggested a possible association between the extent of neurogenesis and cognitive status[5]. We further characterized the effect of ANDRO treatment on hippocampal neurogenesis in APPswe/PS1ΔE9 mice and evaluated the potential contribution of neurogenesis in the effect of ANDRO on spatial memory improvement

Methods

Results

Conclusion