Restoring miR-132 expression rescues adult hippocampal neurogenesis and memory deficits in Alzheimer’s disease

Walgrave, Hannah; Balusu, Sriram; Snoeck, Sarah; Eynden, Elke Vanden; Craessaerts, Katleen; Thrupp, Nicola; Wolfs, Leen; Horré, Katrien; Fourne, Yannick; Ronisz, Alicja; Silajdžić, Edina; Penning, Amber; Tosoni, Giorgia; Callaerts-Végh, Zsuzsanna; D’Hooge, Rudi; Thal, Dietmar Rudolf; Zetterberg, Henrik; Thuret, Sandrine; Fiers, Mark; Frigerio, Carlo Sala; Strooper, Bart De; Salta, Evgenia

doi:10.1016/j.stem.2021.05.001

Cited by 96 publications

(72 citation statements)

References 116 publications

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“…Next, qRT-PCR was performed to validate the expression of the most related miRNA, miR-132-3p. miR-132-3p is abundant in the brain, and accumulating evidence suggests that it plays a crucial role in synaptic plasticity, neurite outgrowth, and memory formation [ 21 – 23 ]. miR-132 deficiency occurs in AD and promotes its pathology [ 24 , 25 ].…”

Section: Resultsmentioning

confidence: 99%

Neurotransmitter-stimulated neuron-derived sEVs have opposite effects on amyloid β-induced neuronal damage

et al. 2021

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The ratio of excitatory to inhibitory neurotransmitters is essential for maintaining the firing patterns of neural networks, and is strictly regulated within individual neurons and brain regions. Excitatory to inhibitory (E/I) imbalance has been shown to participate in the progression of neurodegenerative diseases, including Alzheimer's disease (AD). Glutamate excitotoxicity and GABAergic neuron dysfunction appear to be key components of the neuronal cell death that takes place in AD. Since extracellular vesicles (EVs) are now explored as an important vehicle in transmitting signals between cells, we hypothesized that the function of neuron-derived small EVs (sEVs) might be regulated by the status of neurotransmitter balance and that sEVs might affect amyloid β (Aβ) toxicity on neurons. This study aimed to reveal the effects of sEVs from unbalanced neurotransmitter-stimulated neurons on Aβ-induced toxicity. We demonstrated the opposite effects of the two groups of sEVs isolated from neurons stimulated by glutamate or GABA on Aβ toxicity in vivo and in vitro. The sEVs released from GABA-treated neurons alleviated Aβ-induced damage, while those released from glutamate-treated neurons aggravated Aβ toxicity. Furthermore, we compared the microRNA (miRNA) composition of sEVs isolated from glutamate/GABA/PBS-treated neurons. Our results showed that glutamate and GABA oppositely regulated miR-132 levels in sEVs, resulting in the opposite destiny of recipient cells challenged with Aβ. Our results indicated that manipulating the function of sEVs by different neurotransmitters may reveal the mechanisms underlying the pathogenesis of AD and provide a promising strategy for AD treatment.

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Section: Resultsmentioning

confidence: 99%

Neurotransmitter-stimulated neuron-derived sEVs have opposite effects on amyloid β-induced neuronal damage

et al. 2021

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“…Another neuronal activity-and CREB-regulated miRNA, miR-132, was also previously shown to promote neurite outgrowth, both in cultured cortical neurons via its direct target, p250GAP (Vo et al, 2005), and in vivo (Magill et al, 2010;Luikart et al, 2011;Pathania et al, 2012;Walgrave et al, 2021a). Of note, miR-132 is emerging as a key component of structural plasticity networks regulating dendritic arborization, survival, and synaptic integration, both in postnatal neurogenesis at the SVZ (Pathania et al, 2012) and cell-autonomously, in adult-born neurons in DG (Magill et al, 2010;Luikart et al, 2011;Walgrave et al, 2021a). Conversely, both miR-137 and miR-223 negatively impact dendritic outgrowth in newly born GCs in the adult mouse brain upon retroviral targeting of adult NPCs (Smrt et al, 2010;Harraz et al, 2014).…”

Section: Effects In Physiological Conditions: Late Neurogenic Eventsmentioning

confidence: 98%

“…Interestingly, miR-134 acts by targeting Limk1 in response to neuronal stimulation by BDNF, a key modulator of neuronal plasticity (Schratt et al, 2006). Another neuronal activity-and CREB-regulated miRNA, miR-132, was also previously shown to promote neurite outgrowth, both in cultured cortical neurons via its direct target, p250GAP (Vo et al, 2005), and in vivo (Magill et al, 2010;Luikart et al, 2011;Pathania et al, 2012;Walgrave et al, 2021a). Of note, miR-132 is emerging as a key component of structural plasticity networks regulating dendritic arborization, survival, and synaptic integration, both in postnatal neurogenesis at the SVZ (Pathania et al, 2012) and cell-autonomously, in adult-born neurons in DG (Magill et al, 2010;Luikart et al, 2011;Walgrave et al, 2021a).…”

Section: Effects In Physiological Conditions: Late Neurogenic Eventsmentioning

confidence: 99%

Adult Neural Stem Cell Regulation by Small Non-coding RNAs: Physiological Significance and Pathological Implications

Penning

Tosoni

Abiega

et al. 2022

Front. Cell. Neurosci.

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The adult neurogenic niches are complex multicellular systems, receiving regulatory input from a multitude of intracellular, juxtacrine, and paracrine signals and biological pathways. Within the niches, adult neural stem cells (aNSCs) generate astrocytic and neuronal progeny, with the latter predominating in physiological conditions. The new neurons generated from this neurogenic process are functionally linked to memory, cognition, and mood regulation, while much less is known about the functional contribution of aNSC-derived newborn astrocytes and adult-born oligodendrocytes. Accumulating evidence suggests that the deregulation of aNSCs and their progeny can impact, or can be impacted by, aging and several brain pathologies, including neurodevelopmental and mood disorders, neurodegenerative diseases, and also by insults, such as epileptic seizures, stroke, or traumatic brain injury. Hence, understanding the regulatory underpinnings of aNSC activation, differentiation, and fate commitment could help identify novel therapeutic avenues for a series of pathological conditions. Over the last two decades, small non-coding RNAs (sncRNAs) have emerged as key regulators of NSC fate determination in the adult neurogenic niches. In this review, we synthesize prior knowledge on how sncRNAs, such as microRNAs (miRNAs) and piwi-interacting RNAs (piRNAs), may impact NSC fate determination in the adult brain and we critically assess the functional significance of these events. We discuss the concepts that emerge from these examples and how they could be used to provide a framework for considering aNSC (de)regulation in the pathogenesis and treatment of neurological diseases.

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“…We and other labs have shown that miR-132 is a key miRNA downregulated in the early stages of ADRD before significant neuronal death occurs [ 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 ]. miR-132 overexpression via viral vectors or oligonucleotide mimics exerts neuroprotective effects, delays neurodegeneration, and rescues behavioral deficits in several animal models of ADRD [ 92 , 96 ]. However, targeting miRNAs through a direct small-molecule binder would more likely lead to miR-132 inhibition, as seen for small molecules binding to precursors of other miRNAs [ 24 , 61 , 132 ].…”

Section: Examples Of Adrd-relevant Ncrnas and Screening Strategiesmentioning

confidence: 99%

Small Molecule Drugs Targeting Non-Coding RNAs as Treatments for Alzheimer’s Disease and Related Dementias

Nguyen

Chau

Krichevsky

2021

Genes

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Despite the enormous burden of Alzheimer’s disease and related dementias (ADRD) on patients, caregivers, and society, only a few treatments with limited efficacy are currently available. While drug development conventionally focuses on disease-associated proteins, RNA has recently been shown to be druggable for therapeutic purposes as well. Approximately 70% of the human genome is transcribed into non-protein-coding RNAs (ncRNAs) such as microRNAs, long ncRNAs, and circular RNAs, which can adopt diverse structures and cellular functions. Many ncRNAs are specifically enriched in the central nervous system, and their dysregulation is implicated in ADRD pathogenesis, making them attractive therapeutic targets. In this review, we first detail why targeting ncRNAs with small molecules is a promising therapeutic strategy for ADRD. We then outline the process from discovery to validation of small molecules targeting ncRNAs in preclinical studies, with special emphasis on primary high-throughput screens for identifying lead compounds. Screening strategies for specific ncRNAs will also be included as examples. Key challenges—including selecting appropriate ncRNA targets, lack of specificity of small molecules, and general low success rate of neurological drugs and how they may be overcome—will be discussed throughout the review.

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Restoring miR-132 expression rescues adult hippocampal neurogenesis and memory deficits in Alzheimer’s disease

Cited by 96 publications

References 116 publications

Neurotransmitter-stimulated neuron-derived sEVs have opposite effects on amyloid β-induced neuronal damage

Neurotransmitter-stimulated neuron-derived sEVs have opposite effects on amyloid β-induced neuronal damage

Adult Neural Stem Cell Regulation by Small Non-coding RNAs: Physiological Significance and Pathological Implications

Small Molecule Drugs Targeting Non-Coding RNAs as Treatments for Alzheimer’s Disease and Related Dementias

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