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      Enhancement of neural regeneration as a therapeutic strategy for Alzheimer's disease (Review)

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          Abstract

          Alzheimer's disease (AD), the most common cause of dementia worldwide, has gradually become a global health concern for society and individuals with the process of global ageing. Although extensive research has been carried out on AD, the etiology and pathological mechanism of the disease are still unclear, and there is no specific drug to cure or delay AD progression. The exploration of enhancing nerve regeneration in AD has gradually attracted increasing attention. In the current review, the existing therapeutic strategies were summarized to induce nerve regeneration which can increase the number of neurons, and improve the survival of neurons, the plasticity of synapses and synaptic activity. The strategies include increasing neurotrophic expression (such as brain-derived neurotrophic factor and nerve growth factor), inhibiting acetylcholinesterase (such as donepezil, tacrine, rivastigmine and galanthamine), elevating histone deacetylase levels (such as RGFP-966, Tasquinimod, CM-414 and 44B), stimulating the brain by physiotherapy (such as near-infrared light, repetitive transcranial magnetic stimulation, and transcranial direct current stimulation) and transplanting exogenous neural stem cells. However, further evaluations need to be performed to determine the optimal treatment. The present study reviews recent interventions for enhancing adult neurogenesis and attempts to elucidate their mechanisms of action, which may provide a theoretical basis for inducing nerve regeneration to fight against AD.

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          The cholinergic hypothesis of geriatric memory dysfunction.

          Biochemical, electrophysiological, and pharmacological evidence supporting a role for cholinergic dysfunction in age-related memory disturbances is critically reviewed. An attempt has been made to identify pseudoissues, resolve certain controversies, and clarify misconceptions that have occurred in the literature. Significant cholinergic dysfunctions occur in the aged and demented central nervous system, relationships between these changes and loss of memory exist, similar memory deficits can be artificially induced by blocking cholinergic mechanisms in young subjects, and under certain tightly controlled conditions reliable memory improvements in aged subjects can be achieved after cholinergic stimulation. Conventional attempts to reduce memory impairments in clinical trials hav not been therapeutically successful, however. Possible explanations for these disappointments are given and directions for future laboratory and clinical studies are suggested.
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            Exosome and Exosomal MicroRNA: Trafficking, Sorting, and Function

            Exosomes are 40–100 nm nano-sized vesicles that are released from many cell types into the extracellular space. Such vesicles are widely distributed in various body fluids. Recently, mRNAs and microRNAs (miRNAs) have been identified in exosomes, which can be taken up by neighboring or distant cells and subsequently modulate recipient cells. This suggests an active sorting mechanism of exosomal miRNAs, since the miRNA profiles of exosomes may differ from those of the parent cells. Exosomal miRNAs play an important role in disease progression, and can stimulate angiogenesis and facilitate metastasis in cancers. In this review, we will introduce the origin and the trafficking of exosomes between cells, display current research on the sorting mechanism of exosomal miRNAs, and briefly describe how exosomes and their miRNAs function in recipient cells. Finally, we will discuss the potential applications of these miRNA-containing vesicles in clinical settings.
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              Gamma frequency entrainment attenuates amyloid load and modifies microglia.

              Changes in gamma oscillations (20-50 Hz) have been observed in several neurological disorders. However, the relationship between gamma oscillations and cellular pathologies is unclear. Here we show reduced, behaviourally driven gamma oscillations before the onset of plaque formation or cognitive decline in a mouse model of Alzheimer's disease. Optogenetically driving fast-spiking parvalbumin-positive (FS-PV)-interneurons at gamma (40 Hz), but not other frequencies, reduces levels of amyloid-β (Aβ)1-40 and Aβ 1-42 isoforms. Gene expression profiling revealed induction of genes associated with morphological transformation of microglia, and histological analysis confirmed increased microglia co-localization with Aβ. Subsequently, we designed a non-invasive 40 Hz light-flickering regime that reduced Aβ1-40 and Aβ1-42 levels in the visual cortex of pre-depositing mice and mitigated plaque load in aged, depositing mice. Our findings uncover a previously unappreciated function of gamma rhythms in recruiting both neuronal and glial responses to attenuate Alzheimer's-disease-associated pathology.
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                Author and article information

                Journal
                Exp Ther Med
                Exp Ther Med
                ETM
                Experimental and Therapeutic Medicine
                D.A. Spandidos
                1792-0981
                1792-1015
                September 2023
                01 August 2023
                01 August 2023
                : 26
                : 3
                : 444
                Affiliations
                Department of Physiology and Pharmacology, Health Science Centre, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
                Author notes
                Correspondence to: Professor Liping Li, Department of Physiology and Pharmacology, Health Science Centre, Ningbo University, 818 Fenghua Road, Jiangbei, Ningbo, Zhejiang 315211, P.R. China chulleekribb.re.kr liliping@ 123456nbu.edu.cn
                Article
                ETM-26-3-12143
                10.3892/etm.2023.12143
                10443056
                058072a0-ce61-4615-bd24-b70a14ca9d4a
                Copyright: © Gao et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 09 April 2023
                : 18 July 2023
                Funding
                Funding: The present review was supported by the Zhejiang Provincial Natural Science Foundation of China (grant no. LY23H090004), the Fundamental Research Funds for the Provincial Universities of Zhejiang (grant no. SJLY2023008), the National Natural Science Foundation of China (grant no. 82001155), the Natural Science Foundation of Ningbo (grant no. 2023J068), the College Students' Scientific and Technological Innovation Project (Xin Miao Talent Plan) of Zhejiang Province (grant no. 2022R405A045) and the K. C. Wong Magna Fund in Ningbo University.
                Categories
                Review

                Medicine
                alzheimer's disease,nerve regeneration,neurotrophin,inhibitors,brain stimulation,transplantation

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