A TrkB and TrkC partial agonist restores deficits in synaptic function and promotes activity‐dependent synaptic and microglial transcriptomic changes in a late‐stage Alzheimer's mouse model

Alzheimer s & Dementia, Год журнала: 2024, Номер 20(7), С. 4434 - 4460

Опубликована: Май 23, 2024

Abstract INTRODUCTION Tropomyosin related kinase B (TrkB) and C (TrkC) receptor signaling promotes synaptic plasticity interacts with pathways affected by amyloid beta (Aβ) toxicity. Upregulating TrkB/C could reduce Alzheimer's disease (AD)‐related degenerative signaling, memory loss, dysfunction. METHODS PTX‐BD10‐2 (BD10‐2), a small molecule partial agonist, was orally administered to aged London/Swedish‐APP mutant mice (APP L/S ) wild‐type controls. Effects on hippocampal long‐term potentiation (LTP) were assessed using electrophysiology, behavioral studies, immunoblotting, immunofluorescence staining, RNA sequencing. RESULTS In APP mice, BD10‐2 treatment improved LTP deficits. This accompanied normalized phosphorylation of protein (Akt), calcium‐calmodulin–dependent II (CaMKII), AMPA‐type glutamate receptors containing the subunit GluA1; enhanced activity‐dependent recruitment proteins; increased excitatory synapse number. also had potentially favorable effects LTP‐dependent complement pathway gene transcription. DISCUSSION prevented /Aβ‐associated deficits, reduced abnormalities in synapse‐related transcription genes, bolstered transcriptional changes associated microglial immune response. Highlights Small modulation tropomyosin restores behavior an (AD) model. Modulation TrkB TrkC regulates are candidate targets for translational therapeutics. Electrophysiology combined transcriptomics elucidates restoration. identifies neuron microglia AD‐relevant human‐mouse co‐expression modules.

Язык: Английский

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Promising Strategies to Reduce the SARS-CoV-2 Amyloid Deposition in the Brain and Prevent COVID-19-Exacerbated Dementia and Alzheimer’s Disease

Pharmaceuticals, Год журнала: 2024, Номер 17(6), С. 788 - 788

Опубликована: Июнь 16, 2024

The COVID-19 pandemic, caused by infection with the SARS-CoV-2 virus, is associated cognitive impairment and Alzheimer’s disease (AD) progression. Once it enters brain, virus stimulates accumulation of amyloids in brain that are highly toxic to neural cells. These may trigger neurological symptoms COVID-19. meningeal lymphatic vessels (MLVs) play an important role removal toxins mediate viral drainage from brain. MLVs considered a promising target prevent COVID-19-exacerbated dementia. However, there limited methods for augmentation MLV function. This review highlights new discoveries field COVID-19-mediated amyloid development strategies stimulate clearance through other pathways. based on innovative treating dysfunction induced infection, including use photobiomodulation, plasmalogens, medicinal herbs, which offer hope addressing challenges posed virus.

Язык: Английский

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Radiotherapy for non-cancer diseases: benefits and long-term risks

International Journal of Radiation Biology, Год журнала: 2024, Номер 100(4), С. 505 - 526

Опубликована: Янв. 5, 2024

Purpose The discovery of X-rays was followed by a variety attempts to treat infectious diseases and various other non-cancer with ionizing radiation, in addition cancer. There has been recent resurgence interest the use such radiotherapy for diseases. Non-cancer which currently proposed include refractory ventricular tachycardia, neurodegenerative (e.g. Alzheimer's disease dementia), Coronavirus Disease 2019 (COVID-19) pneumonia, all ongoing clinical studies that deliver radiation doses 0.5–25 Gy single fraction or multiple daily fractions. In effects, historical indications predominantly used some countries Germany) osteoarthritis degenerative bones joints. This narrative review gives an overview biological rationale preclinical diseases, discusses plausibility rationale, considers long-term risks cancer

Язык: Английский

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Insulin restores retinal ganglion cell functional connectivity and promotes visual recovery in glaucoma

Science Advances, Год журнала: 2024, Номер 10(32)

Опубликована: Авг. 7, 2024

Dendrite pathology and synaptic loss result in neural circuit dysfunction, a common feature of neurodegenerative diseases. There is lack strategies that target dendritic regeneration to promote neurorecovery. We show daily human recombinant insulin eye drops stimulate retinal ganglion cell (RGC) dendrite synapse during ocular hypertension, risk factor develop glaucoma. demonstrate the ribosomal protein p70S6 kinase (S6K) essential for insulin-dependent regrowth. Furthermore, S6K phosphorylation stress-activated kinase-interacting 1 (SIN1), link between mammalian rapamycin complexes 2 (mTORC1/2), required insulin-induced regeneration. Using two-photon microscopy live imaging, we rescues single-RGC light-evoked calcium (Ca

Язык: Английский

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Calcineurin inhibition prevents synaptic plasticity deficit induced by brain-derived tau oligomers

Brain Communications, Год журнала: 2024, Номер 6(5)

Опубликована: Янв. 1, 2024

Abstract Compelling evidence suggests that cognitive decline in Alzheimer’s disease is associated with the accumulation and aggregation of tau protein, most toxic aggregates being form oligomers. This underscores necessity for direct isolation analysis brain-derived oligomers from patients disease, potentially offering novel perspectives into toxicity. are potent inhibitors synaptic plasticity; however, involved mechanism still not fully understood. We previously reported a significantly reduced incidence ageing humans chronically treated Food Drug Administration–approved calcineurin inhibitor, FK506 (tacrolimus), used as an immunosuppressant after solid organ transplant. Using combination electrophysiological RNA-sequencing techniques, we provide here has potential to block acute effect on plasticity, well restore levels some key mRNAs. These results further support promising therapeutic strategy treatment disease.

Язык: Английский

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Exploring easily accessible neurophysiological biomarkers for predicting Alzheimer’s disease progression: a systematic review

Alzheimer s Research & Therapy, Год журнала: 2024, Номер 16(1)

Опубликована: Ноя. 4, 2024

Alzheimer disease (AD) remains a significant global health concern. The progression from preclinical stages to overt dementia has become crucial point of interest for researchers. This paper reviews the potential neurophysiological biomarkers in predicting AD progression, based on systematic literature search following PRISMA guidelines, including 55 studies. EEG-based techniques have been predominantly employed, whereas TMS studies are less common. Among investigated measures, spectral power measurements and event-related potentials-based P300 N200 latencies, emerged as most consistent reliable likelihood conversion AD. In addition, TMS-based indices cortical excitability synaptic plasticity also shown assessing risk However, concerns persist regarding methodological discrepancies among studies, accuracy these measures comparison established biomarkers, their immediate clinical applicability. Further research is needed validate predictive capabilities EEG measures. Advancements this area could lead cost-effective, enhancing diagnostic processes deepening our understanding pathophysiology.

Язык: Английский

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Mitochondria transfer as a potential therapeutic mechanism in Alzheimer’s disease-like pathology

Brain Research, Год журнала: 2023, Номер 1819, С. 148544 - 148544

Опубликована: Авг. 22, 2023

Язык: Английский

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Another Use for a Proven Drug: Experimental Evidence for the Potential of Artemisinin and Its Derivatives to Treat Alzheimer’s Disease

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(8), С. 4165 - 4165

Опубликована: Апрель 9, 2024

Plant-derived multitarget compounds may represent a promising therapeutic strategy for multifactorial diseases, such as Alzheimer’s disease (AD). Artemisinin and its derivatives were indicated to beneficially modulate various aspects of AD pathology in different animal models through the regulation wide range cellular processes, energy homeostasis, apoptosis, proliferation inflammatory pathways. In this review, we aimed provide an up-to-date overview experimental evidence documenting neuroprotective activities artemi-sinins underscore potential these already-approved drugs treating also humans propose their consideration carefully designed clinical trials. particular, benefits main pathological hallmarks events cascade throughout development are summarized. Moreover, dose- context-dependent effects artemisinins noted.

Язык: Английский

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Disrupted single-subject gray matter networks are associated with cognitive decline and cortical atrophy in Alzheimer’s disease

Frontiers in Neuroscience, Год журнала: 2024, Номер 18

Опубликована: Май 10, 2024

Research has shown disrupted structural network measures related to cognitive decline and future cortical atrophy during the progression of Alzheimer's disease (AD). However, evidence regarding individual variability gray matter associations with concurrent AD is still sparse.

Язык: Английский

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Edaravone Dexborneol ameliorates the cognitive deficits of APP/PS1 mice by inhibiting TLR4/MAPK signaling pathway via upregulating TREM2

Neuropharmacology, Год журнала: 2024, Номер 255, С. 110006 - 110006

Опубликована: Май 18, 2024

Currently, there are no effective therapeutic agents available to treat Alzheimer's disease (AD). However, edaravone dexborneol (EDB), a novel composite agent used acute ischemic stroke, has recently been shown exert efficacious neuroprotective effects. whether EDB can ameliorate cognitive deficits in AD currently remains unclear. To this end, we explored the effects of on and its potential mechanisms using an animal model (male APP/PS1 mice) treated with for 10 weeks starting at 6 months age. Subsequent analyses revealed that EDB-treated mice exhibited improved abilities compared untreated mice. Administration further alleviated neuropathological alterations hippocampus, including Aβ deposition, pyramidal cell karyopyknosis, oxidative damage, significantly decreased levels inflammatory cytokines (IL-1β, IL-6 TNF-α) COX-2 hippocampus Transcriptome sequencing analysis demonstrated critical role reaction treatment mice, indicating alleviation by was linked action TREM2/TLR4/MAPK signaling pathway. Further vitro investigations showed suppressed neuroinflammation LPS-stimulated BV2 cells inhibiting TLR4/MAPK pathway upregulating TREM2 expression. Thus, findings present study demonstrate is promising AD-related dysfunction.

Язык: Английский

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