<scp>ErbB4</scp> mediates amyloid β‐induced neurotoxicity through <scp>JNK</scp>/tau pathway activation: Implications for Alzheimer's disease

Zhang, Heng; Zhang, Ling; Zhou, Dongming; Li, Hongfei; Yang, Xu

doi:10.1002/cne.25207

Cited by 23 publications

(10 citation statements)

References 74 publications

(119 reference statements)

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“…When neurons release Aβ to the extracellular environment, it would drive other AD pathologies like tau pathology, dendritic and synaptic dysfunction [ 28 , 29 , 42 , 43 ]. Here, western blot and immunofluorescence showed that synaptic proteins as synaptophysin and PSD95 were decreased after treatment with human oligomeric Aβ42 in rodent neurons in accordance with findings in previous studies [ 28 , 44 – 46 ]. Synaptophysin is the major integral membrane protein of synaptic vesicles, functioning in synaptic vesicle cycling, endocytosis, and synaptic plasticity [ 47 ], which is always used as synaptic marker to obtain the reliable data on the morphological organization of the synaptic structures in neurons with the use of confocal laser microscopy.…”

Section: Discussionsupporting

confidence: 92%

Novel small molecular compound 2JY-OBZ4 alleviates AD pathology in cell models via regulating multiple targets

Guo

Huang

et al. 2022

Aging

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Alzheimer's disease (AD) is the most common form of neurodegenerative dementia, characterized by cognitive deficits and memory dysfunction, which is clinically incurable so far. Novel small molecular compound 2JY-OBZ4 is one of structural analogue of Huperzine A (Hup-A), an anti-AD drug in China. In our previous work, 2JY-OBZ4 exhibited potent effects on tau hyperphosphorylation, Aβ production and acetylcholinesterase (AChE) activity. However, 2JY-OBZ4's anti-AD effects and the underlying molecular mechanisms remain unclear. We here reported that 2JY-OBZ4 resisted tau hyperphosphorylation at Thr181 and Ser396 sites in HEK293-hTau cells transfected with GSK-3β, decreased tau phosphorylation via upregulating the activity of PP2A in HEK293-hTau cells and reduced Aβ production through regulating protein levels of APP cleavage enzymes in N2a-hAPP cells. Meanwhile, we found that 2JY-OBZ4 had no adverse effects on cell viability of mice primary neuron even at high concentration, and ameliorated synaptic loss induced by human oligomeric Aβ42. 2JY-OBZ4 had moderate AChE inhibitory activity with the half maximal inhibitory concentration (IC50) to be 39.48 μg/ml in vitro, which is more than two times higher than Hup-A. Together, 2JY-OBZ4 showed promising therapeutic effects in AD cell models through regulating multiple targets. The research provides a new candidate for the therapeutic development of AD.

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Section: Discussionsupporting

confidence: 92%

Novel small molecular compound 2JY-OBZ4 alleviates AD pathology in cell models via regulating multiple targets

Guo

Huang

et al. 2022

Aging

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“…chr5:137291102-137291478+, part of the acetylcholinesterase gene, has been reported to be linked to pathogenesis either by increasing cholinergic deficit or exacerbating Aβ fibril formation and toxicity in AD ( 55 ). Furthermore, chr1:68305845-68396315- is reported to be associated with Erbb4, which mediates amyloid β-induced neurotoxicity via JNK/τ signaling pathway activation ( 56 ). The results demonstrated that compared with the control group, AD mouse brain samples demonstrated increased methylation levels of five circRNAs and decreased methylation levels of three circRNAs.…”

Section: Discussionmentioning

confidence: 99%

Differential methylation of circRNA m6A in an APP/PS1 Alzheimer's disease mouse model

et al. 2023

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Alzheimer's disease (AD) is a chronic neurological disease characterized by memory loss and progressive cognitive impairment. The characteristic AD pathologies include extracellular senile plaques formed by β-amyloid protein deposition, neurofibrillary tangles formed by hyper-phosphorylation of τ protein and neuronal loss caused by glial cell proliferation. However, the pathogenesis of AD is still unclear. Dysregulation of RNA methylation is associated with biological processes, including neurodevelopment and neurodegenerative disease. N6-methyladenosine (m6A) is the main modification in eukaryotic RNA and may be associated with the pathophysiology of AD. Circular RNA (circRNA) is a new type of evolutionarily conserved non-coding RNA without 5'-cap and 3'-polyadenylic acid tail. circRNA undergoes m6A RNA methylation and may be involved in the pathogenesis of AD. In the present study, high-throughput sequencing was performed to assess the degree of circRNA m6A methylation in APP/PS1 AD and C57BL/6 mice. These results suggested that circRNA m6A methylation in AD mice was markedly altered compared to the control group. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis was used to predict associated pathways; genes with different circRNA m6A methylation in AD mice were associated with 'axon guidance', 'long-term potentiation', 'glutamatergic synapse', 'cholinergic synapse', 'GABAergic synapse' and 'long-term depression'. Methylated RNA immunoprecipitation reverse transcription-quantitative PCR demonstrated that among the eight selected circRNA m6A genes, there were five genes that demonstrated significantly increased methylation and three demonstrated significantly decreased methylation.In summary, the present study indicated that circRNA m6A methylation may be associated with pathogenesis of AD.

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“…AlteraPons in ECM components can affect the stability of perineuronal nets, impacPng the clearance of amyloid-β and the producPon of neurofibrillary tangles 21,22 . Signaling pathways such as mTOR, ErbB, and Jak-STAT that are shown to be upregulated in AD parPcipants in this dataset, are known pathways related to the pathogenesis of AD [23][24][25] (Figure 2A). In addiPon, pathways related to Parkinson's disease (PD) and HunPngton's disease (HD) are shown to be significantly dysregulated.…”

Section: Differen%al Expression Of Proteins In Alzheimer's Pa%entsmentioning

confidence: 96%

Identification of Novel Biomarkers for Alzheimer’s Disease and Related Dementias Using Unbiased Plasma Proteomics

Lacar,

Ferdosi,

Alavi

et al. 2024

Preprint

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Alzheimer′s disease (AD) and related dementias (ADRD) is a complex disease with multiple pathophysiological drivers that determine clinical symptomology and disease progression. These diseases develop insidiously over time, through many pathways and disease mechanisms and continue to have a huge societal impact for affected individuals and their families. While emerging blood-based biomarkers, such as plasma p-tau181 and p-tau217, accurately detect Alzheimer neuropthology and are associated with faster cognitive decline, the full extension of plasma proteomic changes in ADRD remains unknown. Earlier detection and better classification of the different subtypes may provide opportunities for earlier, more targeted interventions, and perhaps a higher likelihood of successful therapeutic development. In this study, we aim to leverage unbiased mass spectrometry proteomics to identify novel, blood-based biomarkers associated with cognitive decline. 1,786 plasma samples from 1,005 patients were collected over 12 years from partcipants in the Massachusetts Alzheimer′s Disease Research Center Longitudinal Cohort Study. Patient metadata includes demographics, final diagnoses, and clinical dementia rating (CDR) scores taken concurrently. The Proteograph™ Product Suite (Seer, Inc.) and liquid-chromatography mass-spectrometry (LC-MS) analysis were used to process the plasma samples in this cohort and generate unbiased proteomics data. Data-independent acquisition (DIA) mass spectrometry results yielded 36,259 peptides and 4,007 protein groups. Linear mixed effects models revealed 138 differentially abundant proteins between AD and healthy controls. Machine learning classification models for AD diagnosis identified potential candidate biomarkers including MBP, BGLAP, and APoD. Cox regression models were created to determine the association of proteins with disease progression and suggest CLNS1A, CRISPLD2, and GOLPH3 as targets of further investigation as potential biomarkers. The Proteograph workflow provided deep, unbiased coverage of the plasma proteome at a speed that enabled a cohort study of almost 1,800 samples, which is the largest, deep, unbiased proteomics study of ADRD conducted to date.

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ErbB4 mediates amyloid β‐induced neurotoxicity through JNK/tau pathway activation: Implications for Alzheimer's disease

Cited by 23 publications

References 74 publications

Novel small molecular compound 2JY-OBZ4 alleviates AD pathology in cell models via regulating multiple targets

Novel small molecular compound 2JY-OBZ4 alleviates AD pathology in cell models via regulating multiple targets

Differential methylation of circRNA m6A in an APP/PS1 Alzheimer's disease mouse model

Identification of Novel Biomarkers for Alzheimer’s Disease and Related Dementias Using Unbiased Plasma Proteomics

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