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      Intermittent Hypoxia-Hyperoxia Training Improves Cognitive Function and Decreases Circulating Biomarkers of Alzheimer’s Disease in Patients with Mild Cognitive Impairment: A Pilot Study


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          Alzheimer’s disease (AD) affects not only the central nervous system, but also peripheral blood cells including neutrophils and platelets, which actively participate in pathogenesis of AD through a vicious cycle between platelets aggregation and production of excessive amyloid beta (Aβ). Platelets adhesion on amyloid plaques also increases the risk of cerebral microcirculation disorders. Moreover, activated platelets release soluble adhesion molecules that cause migration, adhesion/activation of neutrophils and formation of neutrophil extracellular traps (NETs), which may damage blood brain barrier and destroy brain parenchyma. The present study examined the effects of intermittent hypoxic-hyperoxic training (IHHT) on elderly patients with mild cognitive impairment (MCI), a precursor of AD. Twenty-one participants (age 51–74 years) were divided into three groups: Healthy Control ( n = 7), MCI+Sham ( n = 6), and MCI+IHHT ( n = 8). IHHT was carried out five times per week for three weeks (total 15 sessions). Each IHHT session consisted of four cycles of 5-min hypoxia (12% F IO 2) and 3-min hyperoxia (33% F IO 2). Cognitive parameters, Aβ and amyloid precursor protein (APP) expression, microRNA 29, and long non-coding RNA in isolated platelets as well as NETs in peripheral blood were investigated. We found an initial decline in cognitive function indices in both MCI+Sham and MCI+IHHT groups and significant correlations between cognitive test scores and the levels of circulating biomarkers of AD. Whereas sham training led to no change in these parameters, IHHT resulted in the improvement in cognitive test scores, along with significant increase in APP ratio and decrease in Aβ expression and NETs formation one day after the end of three-week IHHT. Such effects on Aβ expression and NETs formation remained more pronounced one month after IHHT. In conclusion, our results from this pilot study suggested a potential utility of IHHT as a new non-pharmacological therapy to improve cognitive function in pre-AD patients and slow down the development of AD.

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          Most cited references61

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          Classification and basic pathology of Alzheimer disease.

          The lesions of Alzheimer disease include accumulation of proteins, losses of neurons and synapses, and alterations related to reactive processes. Extracellular Abeta accumulation occurs in the parenchyma as diffuse, focal or stellate deposits. It may involve the vessel walls of arteries, veins and capillaries. The cases in which the capillary vessel walls are affected have a higher probability of having one or two apoepsilon 4 alleles. Parenchymal as well as vascular Abeta deposition follows a stepwise progression. Tau accumulation, probably the best histopathological correlate of the clinical symptoms, takes three aspects: in the cell body of the neuron as neurofibrillary tangle, in the dendrites as neuropil threads, and in the axons forming the senile plaque neuritic corona. The progression of tau pathology is stepwise and stereotyped from the entorhinal cortex, through the hippocampus, to the isocortex. The neuronal loss is heterogeneous and area-specific. Its mechanism is still discussed. The timing of the synaptic loss, probably linked to Abeta peptide itself, maybe as oligomers, is also controversial. Various clinico-pathological types of Alzheimer disease have been described, according to the type of the lesions (plaque only and tangle predominant), the type of onset (focal onset), the cause (genetic or sporadic) and the associated lesions (Lewy bodies, vascular lesions, hippocampal sclerosis, TDP-43 inclusions and argyrophilic grain disease).
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            Patterns of microRNA expression in normal and early Alzheimer's disease human temporal cortex: white matter versus gray matter.

            MicroRNA (miRNA) expression was assessed in human cerebral cortical gray matter (GM) and white matter (WM) in order to provide the first insights into the difference between GM and WM miRNA repertoires across a range of Alzheimer's disease (AD) pathology. RNA was isolated separately from GM and WM portions of superior and middle temporal cerebral cortex (N = 10 elderly females, postmortem interval < 4 h). miRNA profiling experiments were performed using state-of-the-art Exiqon(©) LNA-microarrays. A subset of miRNAs that appeared to be strongly expressed according to the microarrays did not appear to be conventional miRNAs according to Northern blot analyses. Some well-characterized miRNAs were substantially enriched in WM as expected. However, most of the miRNA expression variability that correlated with the presence of early AD-related pathology was seen in GM. We confirm that downregulation of a set of miRNAs in GM (including several miR-15/107 genes and miR-29 paralogs) correlated strongly with the density of diffuse amyloid plaques detected in adjacent tissue. A few miRNAs were differentially expressed in WM, including miR-212 that is downregulated in AD and miR-424 which is upregulated in AD. The expression of certain miRNAs correlates with other miRNAs across different cases, and particular subsets of miRNAs are coordinately expressed in relation to AD-related pathology. These data support the hypothesis that patterns of miRNA expression in cortical GM may contribute to AD pathogenetically, because the aggregate change in miRNA expression observed early in the disease would be predicted to cause profound changes in gene expression.
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              Physiological functions of APP family proteins.

              Biochemical and genetic evidence establishes a central role of the amyloid precursor protein (APP) in Alzheimer disease (AD) pathogenesis. Biochemically, deposition of the β-amyloid (Aβ) peptides produced from proteolytic processing of APP forms the defining pathological hallmark of AD; genetically, both point mutations and duplications of wild-type APP are linked to a subset of early onset of familial AD (FAD) and cerebral amyloid angiopathy. As such, the biological functions of APP and its processing products have been the subject of intense investigation, and the past 20+ years of research have met with both excitement and challenges. This article will review the current understanding of the physiological functions of APP in the context of APP family members.

                Author and article information

                Int J Mol Sci
                Int J Mol Sci
                International Journal of Molecular Sciences
                30 October 2019
                November 2019
                : 20
                : 21
                : 5405
                [1 ]Department of General and Molecular Pathophysiology, Bogomoletz Institute of Physiology, Kyiv 01024, Ukraine; belyak-serebrovska@ 123456hotmail.com (Z.O.S.); ltumanovskaya@ 123456gmail.com (L.V.T.); angela@ 123456biph.kiev.ua (A.M.S.); den-win@ 123456ukr.net (D.A.P.); goncharov@ 123456biph.kiev.ua (S.V.G.); addictive.signals@ 123456gmail.com (D.S.); dosenko@ 123456biph.kiev.ua (V.E.D.)
                [2 ]Department of Hypoxia, Bogomoletz Institute of Physiology, Kyiv 01024, Ukraine
                [3 ]Department of Age Physiology and Pathology of Nervous System, Chebotarev Institute of Gerontology NAMS of Ukraine, Kyiv 04114, Ukraine; victorkholin@ 123456yahoo.com (V.A.K.); n.y.bachinskaya@ 123456gmail.com (N.Y.B.)
                [4 ]Department of Clinical Physiology and Pathology of Internal Organs, Chebotarev Institute of Gerontology NAMS of Ukraine, Kyiv 04114, Ukraine; ksuna.m.o@ 123456ukr.net (O.N.G.); vshatilo@ 123456ukr.net (V.B.S.)
                [5 ]CellAir Constructions GmbH, Schorndorf 73614, Germany; egorov@ 123456cellgym.de
                [6 ]Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0204, USA
                Author notes
                [* ]Correspondence: sereb@ 123456biph.kiev.ua (T.V.S.); lxi@ 123456vcu.edu (L.X.); Tel.: +1-804-6285533 (T.V.S.)
                Author information
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                : 09 October 2019
                : 24 October 2019

                Molecular biology
                alzheimer’s disease,amyloid beta,intermittent hypoxia,hyperoxia,cognitive function,adaptation,platelets,aging,biomarker


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