The prodrug of 7,8-dihydroxyflavone development and therapeutic efficacy for treating Alzheimer’s disease

Chen, Chun; Wang, Wenwen; Zhang, Zhentao; Liu, Xia; Kang, Seong Su; Zhang, Ying; Ye, Keqiang

doi:10.1073/pnas.1718683115

Cited by 132 publications

(126 citation statements)

References 32 publications

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“…To assess the role of gut microbiota alteration in AD pathogenesis, we used the 5XFAD transgenic (Tg) mouse model, which is widely used in AD study for faithfully recapitulating AD-associated pathological features including the severely accelerated cognitive impairment, amyloid deposition in the 2 nd postnatal month, synaptic degeneration in the 4 th postnatal month, and behavioural changes in the 6 th month. [20][21][22][23] Consistent with these reports, [24][25][26][27] we observed rapid accumulation of Aβ plaque deposition in the cortex and hippocampus beginning from the 3 rd postnatal month in Tg mice compared to the age-paired wild-type (WT) mice (Supplementary information, Fig. S1a).…”

Section: Ad Progression Is Associated With the Alteration Of Gut Micrsupporting

confidence: 88%

Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression

Wang¹,

et al. 2019

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Recently, increasing evidence has suggested the association between gut dysbiosis and Alzheimer's disease (AD) progression, yet the role of gut microbiota in AD pathogenesis remains obscure. Herein, we provide a potential mechanistic link between gut microbiota dysbiosis and neuroinflammation in AD progression. Using AD mouse models, we discovered that, during AD progression, the alteration of gut microbiota composition leads to the peripheral accumulation of phenylalanine and isoleucine, which stimulates the differentiation and proliferation of pro-inflammatory T helper 1 (Th1) cells. The brain-infiltrated peripheral Th1 immune cells are associated with the M1 microglia activation, contributing to AD-associated neuroinflammation. Importantly, the elevation of phenylalanine and isoleucine concentrations and the increase of Th1 cell frequency in the blood were also observed in two small independent cohorts of patients with mild cognitive impairment (MCI) due to AD. Furthermore, GV-971, a sodium oligomannate that has demonstrated solid and consistent cognition improvement in a phase 3 clinical trial in China, suppresses gut dysbiosis and the associated phenylalanine/isoleucine accumulation, harnesses neuroinflammation and reverses the cognition impairment. Together, our findings highlight the role of gut dysbiosis-promoted neuroinflammation in AD progression and suggest a novel strategy for AD therapy by remodelling the gut microbiota.

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Section: Ad Progression Is Associated With the Alteration Of Gut Micrsupporting

confidence: 88%

Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression

Wang¹,

et al. 2019

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“…This failure in fl-TrkB localization from non-MLR subcellular regions to buoyant MLRs may explain the lack of efficacy of exogenous neurotrophin delivery in several failed clinical trials. The current study suggests that preservation of MLR-associated fl-TrkB expression in PSAPP-SynCav1 mice may potentially increase the efficacy of endogenous (BDNF) or exogenous agonists (e.g., dihydroxyflavone [28,35,36]) that specifically target TrkB activation. AD brains exhibit anatomical and ultrastructural changes (i.e., reduced synapses) in hippocampal and cortical brain regions [37].…”

Section: Discussionmentioning

confidence: 85%

Synapsin-caveolin-1 Mitigates Cognitive Deficits and Neurodegeneration in PSAPP Mice

Wang

Leem

Podvin

et al. 2020

Preprint

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Background: AD presents with severe neurodegeneration which leads to cognitive deficits and dementia. While many previous approaches focused on targeting amyloid and/or tau, we identified a novel molecular and cellular target that attenuates neurodegeneration in AD which may be exploited as therapeutic targets.Methods: Using immunoblot, microscopic immunofluorescence and proteomic analysis, the current study revealed that PSAPP transgenic mice exhibit decreased hippocampal caveolin-1 (Cav-1), a membrane/lipid raft (MLR) scaffolding protein that organizes synaptic signaling components. Subcellularly, Cav-1 and full length (fl)-TrkB were significantly decreased in hippocampal MLRs. We thus used viral vector that contains a neuronal-targeted Cav-1 construct using the synapsin promoter (SynCav1) to re-express Cav-1 in PSAPP mice. Effects of SynCav1 on cognition function, hippocampal neuron morphology and ultrastructure were examined at 9 (presymptomatic stage) and 11 month (symptomatic stage) respectively.Results: While PSAPP mice showed significant learning and memory deficits at 9 and 11 months, PSAPP mice that received hippocampal SynCav1 (PSAPP-SynCav1) maintained normal learning and memory at 9 and 11 months respectively. Furthermore, PSAPP-SynCav1 mice showed preserved hippocampal MLR-localized fl-TrkB, synaptic ultrastructure, dendritic arborization and axonal myelin content, all of which occurred independent of reducing amyloid deposit and astrogliosis.Conclusions: While transgenic PSAPP mice exhibit decreased hippocampal expression of the MLR scaffolding protein Cav-1 in the early stage of disease, SynCav1 mitigated neuropathology and cognitive deficits in PSAPP mice. Irrespective of amyloid, our approach targeted neuronal degeneration pathways that may be downstream of amyloid species and/or tau in AD but also other forms of neurodegeneration of different or unknown etiology.

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“…It has a very long half-life and improved oral bioavailability. These effects of pro-drug R13 can block synaptic loss though the sustainable induction of TrkB and its downstream signals [120].…”

Section: Other Agentsmentioning

confidence: 99%

Regulation of BDNF-TrkB Signaling and Potential Therapeutic Strategies for Parkinson’s Disease

Jin

2020

JCM

110

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Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase receptor type B (TrkB) are widely distributed in multiple regions of the human brain. Specifically, BDNF/TrkB is highly expressed and activated in the dopaminergic neurons of the substantia nigra and plays a critical role in neurophysiological processes, including neuro-protection and maturation and maintenance of neurons. The activation as well as dysfunction of the BDNF-TrkB pathway are associated with neurodegenerative diseases. The expression of BDNF/TrkB in the substantia nigra is significantly reduced in Parkinson’s Disease (PD) patients. This review summarizes recent progress in the understanding of the cellular and molecular roles of BNDF/TrkB signaling and its isoform, TrkB.T1, in Parkinson’s disease. We have also discussed the effects of current therapies on BDNF/TrkB signaling in Parkinson’s disease patients and the mechanisms underlying the mutation-mediated acquisition of resistance to therapies for Parkinson’s disease.

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The prodrug of 7,8-dihydroxyflavone development and therapeutic efficacy for treating Alzheimer’s disease

Cited by 132 publications

References 32 publications

Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression

Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression

Synapsin-caveolin-1 Mitigates Cognitive Deficits and Neurodegeneration in PSAPP Mice

Regulation of BDNF-TrkB Signaling and Potential Therapeutic Strategies for Parkinson’s Disease

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