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      Therapeutic non-invasive brain treatments in Alzheimer’s disease: recent advances and challenges

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          Abstract

          Alzheimer’s disease (AD) is one of the major neurodegenerative diseases and the most common form of dementia. Characterized by the loss of learning, memory, problem-solving, language, and other thinking abilities, AD exerts a detrimental effect on both patients’ and families’ quality of life. Although there have been significant advances in understanding the mechanism underlying the pathogenesis and progression of AD, there is no cure for AD. The failure of numerous molecular targeted pharmacologic clinical trials leads to an emerging research shift toward non-invasive therapies, especially multiple targeted non-invasive treatments. In this paper, we reviewed the advances of the most widely studied non-invasive therapies, including photobiomodulation (PBM), transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and exercise therapy. Firstly, we reviewed the pathological changes of AD and the challenges for AD studies. We then introduced these non-invasive therapies and discussed the factors that may affect the effects of these therapies. Additionally, we review the effects of these therapies and the possible mechanisms underlying these effects. Finally, we summarized the challenges of the non-invasive treatments in future AD studies and clinical applications. We concluded that it would be critical to understand the exact underlying mechanisms and find the optimal treatment parameters to improve the translational value of these non-invasive therapies. Moreover, the combined use of non-invasive treatments is also a promising research direction for future studies and sheds light on the future treatment or prevention of AD.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s41232-022-00216-8.

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          Neurotoxic reactive astrocytes are induced by activated microglia

          A reactive astrocyte subtype termed A1 is induced after injury or disease of the central nervous system and subsequently promotes the death of neurons and oligodendrocytes.
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            A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease.

            Alzheimer's disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, defining the roles of immune cell subsets in AD onset and progression has been challenging. Using transcriptional single-cell sorting, we comprehensively map all immune populations in wild-type and AD-transgenic (Tg-AD) mouse brains. We describe a novel microglia type associated with neurodegenerative diseases (DAM) and identify markers, spatial localization, and pathways associated with these cells. Immunohistochemical staining of mice and human brain slices shows DAM with intracellular/phagocytic Aβ particles. Single-cell analysis of DAM in Tg-AD and triggering receptor expressed on myeloid cells 2 (Trem2)(-/-) Tg-AD reveals that the DAM program is activated in a two-step process. Activation is initiated in a Trem2-independent manner that involves downregulation of microglia checkpoints, followed by activation of a Trem2-dependent program. This unique microglia-type has the potential to restrict neurodegeneration, which may have important implications for future treatment of AD and other neurodegenerative diseases. VIDEO ABSTRACT.
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              A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β.

              Because it lacks a lymphatic circulation, the brain must clear extracellular proteins by an alternative mechanism. The cerebrospinal fluid (CSF) functions as a sink for brain extracellular solutes, but it is not clear how solutes from the brain interstitium move from the parenchyma to the CSF. We demonstrate that a substantial portion of subarachnoid CSF cycles through the brain interstitial space. On the basis of in vivo two-photon imaging of small fluorescent tracers, we showed that CSF enters the parenchyma along paravascular spaces that surround penetrating arteries and that brain interstitial fluid is cleared along paravenous drainage pathways. Animals lacking the water channel aquaporin-4 (AQP4) in astrocytes exhibit slowed CSF influx through this system and a ~70% reduction in interstitial solute clearance, suggesting that the bulk fluid flow between these anatomical influx and efflux routes is supported by astrocytic water transport. Fluorescent-tagged amyloid β, a peptide thought to be pathogenic in Alzheimer's disease, was transported along this route, and deletion of the Aqp4 gene suppressed the clearance of soluble amyloid β, suggesting that this pathway may remove amyloid β from the central nervous system. Clearance through paravenous flow may also regulate extracellular levels of proteins involved with neurodegenerative conditions, its impairment perhaps contributing to the mis-accumulation of soluble proteins.
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                Author and article information

                Contributors
                lya001@lsuhs.edu
                liutcy@scnu.edu.cn
                duanrui@m.scnu.edu.cn
                Journal
                Inflamm Regen
                Inflamm Regen
                Inflammation and Regeneration
                BioMed Central (London )
                1880-9693
                1880-8190
                3 October 2022
                3 October 2022
                2022
                : 42
                : 31
                Affiliations
                [1 ]GRID grid.263785.d, ISNI 0000 0004 0368 7397, Laboratory of Regenerative Medicine in Sports Science, School of Physical Education and Sports Science, , South China Normal University, ; Guangzhou, 510006 China
                [2 ]GRID grid.411642.4, ISNI 0000 0004 0605 3760, Department of Anesthesiology, , Peking University Third Hospital (PUTH), ; Beijing, 100083 China
                [3 ]GRID grid.411417.6, ISNI 0000 0004 0443 6864, Department of Neurology, , Louisiana State University Health Sciences Center, ; 1501 Kings Highway, Shreveport, LA 71103 USA
                [4 ]GRID grid.410427.4, ISNI 0000 0001 2284 9329, Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, , Augusta University, ; Augusta, GA 30912 USA
                Article
                216
                10.1186/s41232-022-00216-8
                9527145
                36184623
                91b77dcb-6d74-4f0d-ab18-f69862ee61ae
                © The Author(s) 2022

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 9 May 2022
                : 13 June 2022
                Funding
                Funded by: National Key Research and Development Program of China
                Award ID: 2017YFB0403801
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 31971096
                Award ID: 31771256
                Award ID: 32100918
                Award Recipient :
                Funded by: China Postdoctoral Science Foundation
                Award ID: 2021M690060
                Award Recipient :
                Funded by: Sigma Xi Grants in Aid of Research (GIAR) program
                Award ID: G03152021115804390
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2022

                alzheimer’s disease,non-invasive therapy,photobiomodulation,transcranial magnetic stimulation,transcranial direct current stimulation,exercise

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