LMDS-1, a potential TrkB receptor agonist provides a safe and neurotrophic effect for early-phase Alzheimer’s disease

Fan, Chia Hao; Lin, Chia Wei; Huang, Hei Jen; Lee-Chen, Guey Jen; Sun, Yu; Lin, Wenwei; Chen, Chiung Mei; Chang, Kuo Hsuan; Su, Ming; Hsieh-Li, Hsiu Mei

doi:10.1007/s00213-020-05602-z

Cited by 13 publications

(25 citation statements)

References 74 publications

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“…Detection of Gliosis Prevention of Lactulose Administration in the Mouse Hippocampus. Gliosis is an important feature in most neurodegenerative diseases, including AD; 51,54,55 therefore, we also examined the gliosis of astrocytes in the mice. Immunofluorescent staining showed that both lactulose and trehalose significantly inhibited the astrogliosis in the mouse hippocampus that was induced by Aβ toxicity (Figure 5).…”

Section: ■ Resultsmentioning

confidence: 99%

“…The hippocampal proteins of the mice were extracted with an RIPA buffer, and 20 μg protein each was used for a Western blot analysis as previously described. 51 Membranes were incubated with primary antibodies (Table 1) at 4 °C for 16−18 h and HRP-linked secondary antibodies (Table 2) for 1 h at room temperature. The signals were developed by using an ECL kit (Millipore, Billerica, MA, USA).…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

“…MWM was conducted to assess the spatial cognition of mice as previously described. , Four stages were sequentially performed in MWM, including adaptive training (1 day, 1 trial/day), hidden platform training (4 days, 4 trials/days), and hidden platform tests (1 day, 3 trials/days; an index of spatial learning retrieval). Each mouse was placed in the pool for 60 s in each trial.…”

Section: Materials and Methodsmentioning

confidence: 99%

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Prebiotic Lactulose Ameliorates the Cognitive Deficit in Alzheimer’s Disease Mouse Model through Macroautophagy and Chaperone-Mediated Autophagy Pathways

Lee

Lai

Huang

et al. 2021

J. Agric. Food Chem.

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Lactulose, as a prebiotic, can be utilized by human gut microbiota and stimulate their growth. Although microbiota modulation has become an emerging approach to manage many diseases and can be achieved by the administration of prebiotics, fewer investigations have been carried out on the therapeutic mechanism of lactulose. Two trehalose analogs, lactulose and melibiose, were identified as having a neuroprotective effect in polyglutamine and Parkinson disease models. In this study, we examined lactulose and melibiose in a mouse primary hippocampal neuronal culture under the toxicity of oligomeric Aβ25–35. Lactulose was further tested in vivo because its effective concentration is lower than that of melibiose. Lactulose and trehalose were applied individually to mice before a bilateral intrahippocampal CA1 injection of oligomeric Aβ25–35. The administration of lactulose and trehalose attenuated the short-term memory and the learning retrieval of Alzheimer’s disease (AD) mice. From a pathological analysis, we found that the pretreatment of lactulose and trehalose decreased neuroinflammation and increased the levels of the autophagic pathways. These results suggest that the neuroprotective effects of both lactulose and trehalose are achieved through anti-inflammation and autophagy. In addition, lactulose was better than trehalose in the enhancement of the synaptic protein expression level in AD mice. Therefore, lactulose could potentially be developed into a preventive and/or therapeutic disaccharide for AD.

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Section: ■ Resultsmentioning

confidence: 99%

Section: ■ Materials and Methodsmentioning

confidence: 99%

Section: Materials and Methodsmentioning

confidence: 99%

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Prebiotic Lactulose Ameliorates the Cognitive Deficit in Alzheimer’s Disease Mouse Model through Macroautophagy and Chaperone-Mediated Autophagy Pathways

Lee

Lai

Huang

et al. 2021

J. Agric. Food Chem.

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“…In the future, investigating if PI3K/AKT/mTOR is also involved in the neuroprotective mechanism of these flavones is warranted. Besides, although our previous study has shown the neuroprotection effects of 7,8-DHF in the primary hippocampal primary neurons and mouse models induced by Aβ (Fan et al, 2020), whether the other two flavones apigenin and quercetin also provide the similar effects either in primary neurons and mouse models should be examined in the future.…”

Section: Discussionmentioning

confidence: 97%

“…Furthermore, an optimized 7,8-DHF prodrug R13 alleviates Aβ deposition, attenuates the loss of hippocampal synapse, and ameliorates memory deficits in 5 × FAD mice ( Chen et al, 2018 ). We have previously shown neuroprotective effects of 7,8-DHF on neurite length and branch in mouse hippocampal primary neurons under Aβ toxicity and 7,8-DHF-mediated upregulation of neuronal nuclei, p-ERK, and p-CREB in the immunohistochemical staining of mice with oligomeric Aβ injection into hippocampal cornu ammonis area 1 subregion ( Fan et al, 2020 ). In addition, wogonin (5,7-dihydroxy-8-methoxyflavone), a novel inhibitor for mammalian target of rapamycin (mTOR) signaling pathway, strengthens the autophagy to effectively clear Aβ and suppresses Tau protein phosphorylation ( Zhu and Wang, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Flavones 7,8-DHF, Quercetin, and Apigenin Against Tau Toxicity via Activation of TRKB Signaling in ΔK280 TauRD-DsRed SH-SY5Y Cells

Chiang

Lin

Teng

et al. 2021

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease with memory loss and cognitive decline. Neurofibrillary tangles (NFTs) formed by hyperphosphorylated Tau protein are one of the pathological hallmarks of several neurodegenerative diseases including AD. Heat shock protein family B (small) member 1 (HSPB1) is a molecular chaperone that promotes the correct folding of other proteins in response to environmental stress. Nuclear factor erythroid 2-like 2 (NRF2), a redox-regulated transcription factor, is the master regulator of the cellular response to excess reactive oxygen species. Tropomyosin-related kinase B (TRKB) is a membrane-bound receptor that, upon binding brain-derived neurotrophic factor (BDNF), phosphorylates itself to initiate downstream signaling for neuronal survival and axonal growth. In this study, four natural flavones such as 7,8-dihydroxyflavone (7,8-DHF), wogonin, quercetin, and apigenin were evaluated for Tau aggregation inhibitory activity and neuroprotection in SH-SY5Y neuroblastoma. Among the tested flavones, 7,8-DHF, quercetin, and apigenin reduced Tau aggregation, oxidative stress, and caspase-1 activity as well as improved neurite outgrowth in SH-SY5Y cells expressing ΔK280 TauRD-DsRed folding reporter. Treatments with 7,8-DHF, quercetin, and apigenin rescued the reduced HSPB1 and NRF2 and activated TRKB-mediated extracellular signal-regulated kinase (ERK) signaling to upregulate cAMP-response element binding protein (CREB) and its downstream antiapoptotic BCL2 apoptosis regulator (BCL2). Knockdown of TRKB attenuated the neuroprotective effects of these three flavones. Our results suggest 7,8-DHF, quercetin, and apigenin targeting HSPB1, NRF2, and TRKB to reduce Tau aggregation and protect cells against Tau neurotoxicity and may provide new treatment strategies for AD.

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Targeting brain‐derived neurotrophic factor in the treatment of neurodegenerative diseases: A review

Wang,

Lang,

Wei

et al. 2024

Neuroprotection

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Neurodegenerative diseases, marked by the gradual death of neurons, present a significant and growing public health challenge. Brain‐derived neurotrophic factor (BDNF) is crucial for the survival, development, and synaptic plasticity of neurons. Studies have consistently demonstrated that perturbed BDNF communication pathways are associated with the development and progression of neurodegenerative conditions, underscoring their potential as therapeutic targets. This review aimed to summarize the existing findings regarding BDNF expression, metabolism, and signaling transduction. Furthermore, we reviewed the intricate roles of BDNF signaling pathways in neurodegenerative diseases, elucidating their contributions to disease onset and progression. The latest advancements in targeting BDNF for the treatment of neurodegenerative diseases, including the development of small molecules, nucleic acid‐based therapeutics, and antibody‐based approaches, were also summarized. Despite recent strides, challenges persist, including a lack of comprehensive understanding of BDNF modulation across diverse neurodegenerative contexts and the absence of clinically approved BDNF‐targeted drugs.

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LMDS-1, a potential TrkB receptor agonist provides a safe and neurotrophic effect for early-phase Alzheimer’s disease

Cited by 13 publications

References 74 publications

Prebiotic Lactulose Ameliorates the Cognitive Deficit in Alzheimer’s Disease Mouse Model through Macroautophagy and Chaperone-Mediated Autophagy Pathways

Prebiotic Lactulose Ameliorates the Cognitive Deficit in Alzheimer’s Disease Mouse Model through Macroautophagy and Chaperone-Mediated Autophagy Pathways

Flavones 7,8-DHF, Quercetin, and Apigenin Against Tau Toxicity via Activation of TRKB Signaling in ΔK280 TauRD-DsRed SH-SY5Y Cells

Targeting brain‐derived neurotrophic factor in the treatment of neurodegenerative diseases: A review

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