Synaptic degeneration and neurogranin in the pathophysiology of Alzheimer’s disease

Lista, Simone; Hampel, Harald

doi:10.1080/14737175.2016.1204234

Cited by 74 publications

(45 citation statements)

References 93 publications

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“…NEUG is primarily expressed in the brain [ 37 ] and is the main postsynaptic protein regulating the availability of Calmodulin by binding to it in the absence of Ca 2+ [ 38 ]. Here, signal intensities of 6 unique peptides were lower in LS in comparison to the remainder of samples (VS, LC, VC) (Fig.…”

Section: Resultsmentioning

confidence: 99%

The effect of DPP-4 inhibition to improve functional outcome after stroke is mediated by the SDF-1α/CXCR4 pathway

Chiazza

Tammen

Pintana

et al. 2018

Cardiovasc Diabetol

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BackgroundDipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) are approved drugs for the treatment of hyperglycemia in patients with type 2 diabetes. These effects are mainly mediated by inhibiting endogenous glucagon-like peptide-1 (GLP-1) cleavage. Interestingly, gliptins can also improve stroke outcome in rodents independently from GLP1. However, the underlying mechanisms are unknown. Stromal cell-derived factor-1α (SDF-1α) is a DPP-4 substrate and CXCR4 agonist promoting beneficial effects in injured brains. However, SDF-1α involvement in gliptin-mediated neuroprotection after ischemic injury is unproven. We aimed to determine whether the gliptin linagliptin improves stroke outcome via the SDF-1α/CXCR4 pathway, and identify additional effectors behind the efficacy.MethodsMice were subjected to stroke by transient middle cerebral artery occlusion (MCAO). linagliptin was administered for 3 days or 3 weeks from stroke onset. The CXCR4-antagonist AMD3100 was administered 1 day before MCAO until 3 days thereafter. Stroke outcome was assessed by measuring upper-limb function, infarct volume and neuronal survival. The plasma and brain levels of active GLP-1, GIP and SDF-1α were quantified by ELISA. To identify additional gliptin-mediated molecular effectors, brain samples were analyzed by mass spectrometry.ResultsLinagliptin specifically increased active SDF-1α but not glucose-dependent insulinotropic peptide (GIP) or GLP-1 brain levels. Blocking of SDF-1α/CXCR4 pathway abolished the positive effects of linagliptin on upper-limb function and histological outcome after stroke. Moreover, linagliptin treatment after stroke decreased the presence of peptides derived from neurogranin and from an isoform of the myelin basic protein.ConclusionsWe showed that linagliptin improves functional stroke outcome in a SDF-1α/CXCR4-dependent manner. Considering that Calpain activity and intracellular Ca2+ regulate neurogranin and myelin basic protein detection, our data suggest a gliptin-mediated neuroprotective mechanism via the SDF-1α/CXCR4 pathway that could involve the regulation of Ca2+ homeostasis and the reduction of Calpain activity. These results provide new insights into restorative gliptin-mediated effects against stroke.Electronic supplementary materialThe online version of this article (10.1186/s12933-018-0702-3) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

The effect of DPP-4 inhibition to improve functional outcome after stroke is mediated by the SDF-1α/CXCR4 pathway

Chiazza

Tammen

Pintana

et al. 2018

Cardiovasc Diabetol

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“…The pathogenesis of this complex polygenic neurodegenerative disease (ND) involves sequentially interacting pathophysiological cascades, including both core events – i.e., accumulation of the forty-two-amino acid-long amyloid beta (Aβ 42 ) peptide into amyloid plaques and self-aggregation of hyperphosphorylated tau protein to form intraneuronal neurofibrillary tangles – and downstream processes, such as generalized neuroinflammation [2, 3]. These events induce axonal degeneration [4–6] and disruption of synaptic integrity [7, 8], thus leading to synaptic dysfunction and, ultimately, deterioration of physiological neural connectivity [9]. …”

Section: Introductionmentioning

confidence: 99%

Revolution of Alzheimer Precision Neurology. Passageway of Systems Biology and Neurophysiology

Hampel

Toschi

Babiloni

et al. 2018

JAD

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132

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The Precision Neurology development process implements systems theory with system biology and neurophysiology in a parallel, bidirectional research path: a combined hypothesis-driven investigation of systems dysfunction within distinct molecular, cellular and large-scale neural network systems in both animal models as well as through tests for the usefulness of these candidate dynamic systems biomarkers in different diseases and subgroups at different stages of pathophysiological progression. This translational research path is paralleled by an “omics”-based, hypothesis-free, exploratory research pathway, which will collect multimodal data from progressing asymptomatic, preclinical and clinical neurodegenerative disease (ND) populations, within the wide continuous biological and clinical spectrum of ND, applying high-throughput and high-content technologies combined with powerful computational and statistical modeling tools, aimed at identifying novel dysfunctional systems and predictive marker signatures associated with ND. The goals are to identify common biological denominators or differentiating classifiers across the continuum of ND during detectable stages of pathophysiological progression, characterize systems-based intermediate endophenotypes, validate multi-modal novel diagnostic systems biomarkers, and advance clinical intervention trial designs by utilizing systems-based intermediate endophenotypes and candidate surrogate markers. Achieving these goals is key to the ultimate development of early and effective individualized treatment of ND, such as Alzheimer’s disease (AD). The Alzheimer Precision Medicine Initiative (APMI) and cohort program (APMI-CP), as well as the Paris based core of the Sorbonne University Clinical Research Group “Alzheimer Precision Medicine” (GRC-APM) were recently launched to facilitate the passageway from conventional clinical diagnostic and drug development towards breakthrough innovation based on the investigation of the comprehensive biological nature of aging individuals. The APMI movement is gaining momentum to systematically apply both systems neurophysiology and systems biology in exploratory translational neuroscience research on ND.

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“…В основе патогенеза этого сложного полигенного нейродегенеративного заболевания находится последовательное взаимодействие патофизиологических каскадов, в том числе основных событий -т. е., накопление бетаамилоида (aβ42) пептида в амилоидных бляшек и собственной hyperphosphorylated агрегацию тау-белка в форме intraneuronal neurofibrillary -и технологических процессов, таких как нейровоспаления [15,16]. Эти события вызывают аксональную дегенерацию 17-19], и нарушение синаптической целостности [20,21], что приводит к синаптической дисфункции и, в конечном счете, ухудшению физиологической нейронной связности [22].…”

Section: болезньunclassified

Alzheimer’s Disease and Artificial Intelligence: Long-term Personalized Rehabilitation and Medical and Social Support

Bulgakova

Romanchuk

et al. 2019

BSP

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Modern technologies and tools for the rehabilitation of patients with Alzheimer’s disease have many potential applications for the treatment of dementia from diagnosis and evaluation to medical care, medical, social and economic support: from healthy aging, to accelerated and pathological aging of Homo sapiens. Doctor and neuroscientist: a modern solution to problems of rehabilitation ‘cognitive brain’ of Homo sapiens using on the one hand, tools and technologies of artificial intelligence, and with another — a multidisciplinary collaboration with clinical neurophysiologist ‘universal’ specialist in the field of neurology, psychiatry, psychotherapy, psychoanalysis and geriatrics. Systems biology, Biophysics, physiology, neurophysiology and highlight the multidimensional and combinatorial profiles of genetic, biological, pathophysiological and clinical biomarkers that reflects the heterogeneity of neurodegeneration, by means of modern efficient analysis tools to register and create comprehensive maps of the brain and recording of dynamic models in different systems: from molecules to neurons to brain regions. Bioinformatics, neuroimaging and neurophysiology of systems are aimed at calculating neural network models of the relationship between structure and dynamic function in brain networks. Structural and functional markers of the brain establish a link between clinical phenotypes and molecular pathophysiological mechanisms. Phenotypic variability is now considered one of the biggest problems in gerontology and geriatrics. MRI imaging to detect subtle changes in brain tissue and structure, fMRI imaging to measure changes in brain activity, and EEG to measure electrical activity have given clinicians many new insights into what happens in the brain in healthy and pathological aging. The paradigm of system neurophysiology is aimed at studying the fundamental principles of functioning of integrated neural systems through the integration and analysis of neural information recorded in a multimodal way (for example, fMRI and EEG), through computational modeling and combining data mining methods. The ultimate goal of systemic neurophysiology is to find out how signals are represented in neocortical networks and what role many different neural components play. Modern artificial intelligence technologies are capable of many things, including predicting Alzheimer's disease with the help of combined and hybrid neuroimaging, sequencing of a new generation, etc., in order to start timely and effective rehabilitation brain Homo sapiens.

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Synaptic degeneration and neurogranin in the pathophysiology of Alzheimer’s disease

Cited by 74 publications

References 93 publications

The effect of DPP-4 inhibition to improve functional outcome after stroke is mediated by the SDF-1α/CXCR4 pathway

The effect of DPP-4 inhibition to improve functional outcome after stroke is mediated by the SDF-1α/CXCR4 pathway

Revolution of Alzheimer Precision Neurology. Passageway of Systems Biology and Neurophysiology

Alzheimer’s Disease and Artificial Intelligence: Long-term Personalized Rehabilitation and Medical and Social Support

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