Electromagnetized gold nanoparticles improve neurogenesis and cognition in the aged brain

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  Electromagnetized gold nanoparticles improve neurogenesis and cognition in the aged brain

  Author links open overlay panelYujungChang^aByounggookCho^aEuiyeonLee^bJunyeopKim^aJunsangYoo^cJung-SukSung^dYoungeunKwon^b

  JongpilKim^ab

  https://doi.org/10.1016/j.biomaterials.2021.121157Get rights and content

  Abstract

  Adult neurogenesis is the lifelong process by which new neurons are generated in the dentate gyrus. However, adult neurogenesis capacity decreases with age, and this decrease is closely linked to cognitive and memory decline. Our study demonstrated that electromagnetized gold nanoparticles (AuNPs) promote adult hippocampal neurogenesis, thereby improving cognitive function and memory consolidation in aged mice. According to single-cell RNA sequencing data, the numbers of neural stem cells (NSCs) and neural progenitors were significantly increased by electromagnetized AuNPs. Additionally, electromagnetic stimulation resulted in specific activation of the histone acetyltransferase Kat2a, which led to histone H3K9 acetylation in adult NSCs. Moreover, in vivo electromagnetized AuNP stimulation efficiently increased hippocampal neurogenesis in aged and Hutchinson-Gilford progeria mouse brains, thereby alleviating the symptoms of aging. Therefore, our study provides a proof-of-concept for the in vivo stimulation of hippocampal neurogenesis using electromagnetized AuNPs as a promising therapeutic strategy for the treatment of age-related brain diseases.

  Introduction

  Neurogenesis is the process by which new neurons are generated in the brain, which involves cell proliferation and differentiation [[1], [2], [3]]. In the hippocampus, neurogenesis mainly occurs in the subgranular zone (SGZ) of the dentate gyrus, wherein neural stem cells (NSCs) reside [2,3]. NSCs in the SGZ undergo self-renewal and differentiation processes to become neural progenitor cells and neuroblasts, after which they become mature neurons [4,5]. Although the functional roles of neurogenesis in the adult brain remain largely unclear, adult hippocampal neurogenesis has been associated with various cognitive functions including associative learning, novel object recognition, and even long-term memory formation [[6], [7], [8]]. Therefore, adult neurogenesis may enhance synaptic plasticity in the hippocampus, thus improving cognitive functions including learning and memory [9,10].

  Mammalian neurogenesis is affected by various factors including age, stress, sleep, caloric restriction, exercise, and physiology [[11], [12], [13], [14], [15], [16], [17]]. In particular, hippocampal neurogenesis is dramatically decreased during aging, which is closely associated with cognitive impairment in the aged brain [[18], [19], [20]]. Therefore, promoting neurogenesis in the aged brain is a potentially viable therapeutic strategy for the treatment of age-associated cognitive impairment. In fact, several studies have reported that increasing adult neurogenesis ameliorates learning and memory impairment in aged individuals [[12], [13], [14],16,17,21]. For example, exercise-mediated improvements in blood plasma properties enhanced neurogenesis and improved learning and memory in aged mice [16]. In another study, overexpression of miR153 significantly increased neurogenesis and reverted cognitive impairment in aged mice [17]. Moreover, treating the dentate gyrus of aged mice with FGF-2 and EGF increased BrdU-labeled proliferating NSCs [13]. Additionally, resveratrol, a food-derived compound, stimulated the proliferation and survival of NSCs, which promoted the generation of new neurons in the hippocampus and enhanced hippocampal functions in an aged mouse model [22]. Collectively, these studies suggest that induction of neurogenesis in the hippocampus may reduce neurodegeneration and can be a promising therapeutic strategy for the treatment of age-related neurodegenerative diseases.

  Emerging evidence has demonstrated that physical stimuli can affect cell fate conversion and modify stem cell behavior [11,[23], [24], [25]]. Among the various physical stimuli, multifunctional nanoparticle-mediated physical stimuli have attracted attention due to their various applications in stem cell and gene delivery-based therapies [26]. In particular, gold nanoparticles (AuNPs) have been widely used as delivery carriers and therapeutic agents for biomedical applications due to their unique properties, such as their ease of synthesis and versatility in surface functionalization. For example, recent studies have reported that AuNPs conjugated with retinoic acid were used to promote cell proliferation and differentiation of stem cells in vitro [27,28]. Moreover, we previously demonstrated that electromagnetized AuNPs could be used for efficient direct lineage reprogramming of somatic cells into induced dopamine neurons in vivo [25], which demonstrates the feasibility of AuNPs-mediated magnetic stimulation as a novel therapeutic for Parkinson's disease.

  In this study, we demonstrate that AuNPs exposed to electromagnetic field (EMF) stimulated adult brain NSCs in the dentate gyrus of the hippocampus, which significantly increased hippocampal neurogenesis in the adult mouse brain and alleviated the age-associated cognitive impairment symptoms in the aged brain (Fig. 1a). We confirmed the specific activation of active hippocampal NSCs in response to treatment with electromagnetized AuNPs at the single-cell level. Moreover, we found that electromagnetized AuNPs alter H3K9 histone acetylation via induction of the histone acetyltransferase Kat2a in NSCs, suggesting that electromagnetized AuNPs increase the genome accessibility of adult NSCs and facilitate the activation of hippocampal neurogenesis. Importantly, electromagnetic stimulation enhanced hippocampal neurogenesis in brains from aged and progeria mice, thereby improving cognitive functions including learning and memory. Therefore, our findings demonstrate that in vivo EMF stimulation is a promising strategy for the controllable and efficient activation of adult brain NSCs. Thus, our results indicate that electromagnetic stimulation by EMF-exposed AuNPs may represent a viable therapeutic strategy for the restoration of neuronal populations from adult brain NSCs in aged brains.

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