Synaptic Dysfunction in Alzheimer’s Disease: Aβ, Tau, and Epigenetic Alterations

Li, Ké; Qing, Wei; Liu, Fangfang; Hu, Fan; Xie, Ao-Ji; Zhu, Ling‐Qiang; Liú, Dan

doi:10.1007/s12035-017-0533-3

Cited by 80 publications

(62 citation statements)

References 144 publications

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“…Next, we examined the exact underlying mechanisms of MT2’s protective effects against Aβ42‐induced dendritic injuries. Recently, the roles of microRNAs (miRNAs) in synaptic disorder observed in AD have been well elucidated (Li et al, ; Liu et al, ; Wang et al, ). Therefore, we then measured the expression of brain‐enriched miRNAs that had been reported previously upon the different treatments above.…”

Section: Resultsmentioning

confidence: 99%

Activation of MT2 receptor ameliorates dendritic abnormalities in Alzheimer’s disease via C/EBPα/miR‐125b pathway

Tang

Wang

et al. 2019

Aging Cell

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Impairments of dendritic trees and spines have been found in many neurodegenerative diseases, including Alzheimer's disease (AD), in which the deficits of melatonin signal pathway were reported. Melatonin receptor 2 (MT2) is widely expressed in the hippocampus and mediates the biological functions of melatonin. It is known that melatonin application is protective to dendritic abnormalities in AD. However, whether MT2 is involved in the neuroprotection and the underlying mechanisms are not clear. Here, we first found that MT2 is dramatically reduced in the dendritic compartment upon the insult of oligomer Aβ. MT2 activation prevented the Aβ‐induced disruption of dendritic complexity and spine. Importantly, activation of MT2 decreased cAMP, which in turn inactivated transcriptional factor CCAAT/enhancer‐binding protein α(C/EBPα) to suppress miR‐125b expression and elevate the expression of its target, GluN2A. In addition, miR‐125b mimics fully blocked the protective effects of MT2 activation on dendritic trees and spines. Finally, injection of a lentivirus containing a miR‐125b sponge into the hippocampus of APP/PS1 mice effectively rescued the dendritic abnormalities and learning/memory impairments. Our data demonstrated that the cAMP‐C/EBPα/miR‐125b/GluN2A signaling pathway is important to the neuroprotective effects of MT2 activation in Aβ‐induced dendritic injuries and learning/memory disorders, providing a novel therapeutic target for the treatment of AD synaptopathy.

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Section: Resultsmentioning

confidence: 99%

Activation of MT2 receptor ameliorates dendritic abnormalities in Alzheimer’s disease via C/EBPα/miR‐125b pathway

Tang

Wang

et al. 2019

Aging Cell

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“…Tau hyperphosphorylation leads to the Tau/Fyn/PSD-95/NMDAR complex dissociation disrupting LTP-required synaptic potentiation (Frandemiche et al, 2014), reducing the number of functional DS (Tracy and Gan, 2018). In addition, hyperphosphorylated tau missorting into somatodendritic compartments promotes NMDAR overactivation, followed by Ca 2+ influx and cytotoxicity (Li et al, 2018). However, further functional studies are necessary to determinate the key cytoskeleton-associated components in the tau-induced toxicity.…”

Section: Synaptic Plasticity Impairment In Alzheimer's Diseasementioning

confidence: 99%

Dendritic Spine and Synaptic Plasticity in Alzheimer’s Disease: A Focus on MicroRNA

Reza-Zaldívar¹,

Hernández-Sapiéns²,

Minjarez

et al. 2020

Front. Cell Dev. Biol.

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Dendrites and dendritic spines are dynamic structures with pivotal roles in brain connectivity and have been recognized as the locus of long-term synaptic plasticity related to cognitive processes such as learning and memory. In neurodegenerative diseases, the spine dynamic morphology alteration, such as shape and spine density, affects functional characteristics leading to synaptic dysfunction and cognitive impairment. Recent evidence implicates dendritic spine dysfunction as a critical feature in the pathogenesis of dementia, particularly Alzheimer's disease. The alteration of spine morphology and their loss is correlated with the cognitive decline in Alzheimer's disease patients even in the absence of neuronal loss, however, the underlying mechanisms are poorly understood. Currently, the microRNAs have emerged as essential regulators of synaptic plasticity. The changes in neuronal microRNA expression that contribute to the modification of synaptic function through the modulation of dendritic spine morphology or by regulating the local protein translation to synaptic transmission are determinant for synapse formation and synaptic plasticity. Focusing on microRNA and its targets may provide insight into new therapeutic opportunities. In this review we summarize the experimental evidence of the role that the microRNA plays in dendritic spine remodeling and synaptic plasticity and its potential therapeutic approach in Alzheimer's disease. Targeting synaptic deficits through the structural alteration of dendritic spines could form part of therapeutic strategies to improve synaptic plasticity and to ameliorate cognitive impairments in Alzheimer's disease and other neurological diseases.

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“…64 Besides the substantial and irreversible loss of hippocampal neurons, decline in synaptic integrity and neurotransmission within various brain circuitries is prominent in AD. 65 The accumulation of Aβ and tau proteins, [65][66][67][68] mitochondrial dysfunction, 67,69 and oxidative stress 67,70 has been demonstrated to suppress and enhance the longterm potentiation (LTP) and long-term depression (LTD) of synaptic strength in the hippocampus, respectively. These changes of LTP and LTD at mature neurons have been shown to limit the release of neurotransmitters and growth factors, thereby hindering the differentiation and integration of the newborn neurons into the hippocampal circuitries.…”

Section: Mechanisms Of Impaired Neurogenesis In Admentioning

confidence: 99%

Therapeutic potential of neurogenesis and melatonin regulation in Alzheimer's disease

Mihardja

Roy

Wong

et al. 2020

Annals of the New York Academy of Sciences

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Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by the hallmark pathologies of amyloid-beta plaques and neurofibrillary tangles. Symptoms of this devastating disease include behavioral changes and deterioration of higher cognitive functions. Impairment of neurogenesis has also been shown to occur in AD, which adversely impacts new neuronal cell growth, differentiation, and survival. This impairment possibly results from the cumulative effects of the various pathologies of AD. Preclinical studies have suggested that the administration of melatonin-the pineal hormone primarily responsible for the regulation of the circadian rhythm-targets the effects of AD pathologies and improves cognitive impairment. It is postulated that by mitigating the effect of these pathologies, melatonin can also rescue neurogenesis impairment. This review aims to explore the effect of AD pathologies on neurogenesis, as well as the mechanisms by which melatonin is able to ameliorate AD pathologies to potentially promote neurogenesis.

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Synaptic Dysfunction in Alzheimer’s Disease: Aβ, Tau, and Epigenetic Alterations

Cited by 80 publications

References 144 publications

Activation of MT2 receptor ameliorates dendritic abnormalities in Alzheimer’s disease via C/EBPα/miR‐125b pathway

Activation of MT2 receptor ameliorates dendritic abnormalities in Alzheimer’s disease via C/EBPα/miR‐125b pathway

Dendritic Spine and Synaptic Plasticity in Alzheimer’s Disease: A Focus on MicroRNA

Therapeutic potential of neurogenesis and melatonin regulation in Alzheimer's disease

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