Roles and Mechanisms of Axon-Guidance Molecules in Alzheimer’s Disease

Zhang, Lei; Qi, Zhipeng; Li, Jiashuo; Li, Minghui; Du, Xianchao; Wang, Shuang; Zhou, Guoyu; Xu, Bin; Liu, Wei; Shi, Xi; Xu, Zuojun; Deng, Yu

doi:10.1007/s12035-021-02311-2

Cited by 37 publications

(27 citation statements)

References 175 publications

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“…Our in-silico functional analysis predicted 26 miRNAs that could bind the three abundant circPSEN1 species. These 26 miRNAs are significantly associated with several pathways, including wnt, hippo and axon guidance pathways that have been previously related to the development of AD and to neuroinflammation [42][43][44][45]. Among the 26 identified miRNAs, miR-144 has previously been associated…”

Section: -Discussionmentioning

confidence: 95%

Circular RNA detection identifiescircPSEN1alterations in brain specific to Autosomal Dominant Alzheimer Disease

Chen

Eteleeb

Wang

et al. 2021

Preprint

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BackgroundAutosomal-dominant Alzheimer’s disease (ADAD) is caused by pathogenic mutations in APP, PSEN1, and PSEN2, which usually lead to an early age at onset (<65). Circular RNAs are a family of non-coding RNAs highly expressed in the nervous system and especially in synapses. We aimed to investigate differences in brain gene expression of linear and circular transcripts from the three ADAD genes in controls, sporadic AD, and ADAD.MethodsWe obtained and sequenced RNA from brain cortex using standard protocols. Linear counts were obtained using the TOPMed pipeline; circular counts, using python package DCC. After stringent quality control (QC), we obtained the counts for PSEN1, PSEN2 and APP genes. Only circPSEN1 passed QC. We used DESeq2 to compare the counts across groups, correcting for biological and technical variables. Finally, we performed in-silico functional analyses using the Circular RNA interactome website and DIANA mirPath software.ResultsOur results show significant differences in gene counts of circPSEN1 in ADAD individuals, when compared to sporadic AD and controls (ADAD=22, AD=274, Controls=25 – ADADvsCO: log2FC=0.786, p=9.08×10-05, ADADvsAD: log2FC=0.576, p=2.00×10-03). The high gene counts are contributed by two circPSEN1 species (hsa_circ_0008521 and hsa_circ_0003848). No significant differences were observed in linear PSEN1 gene expression between cases and controls, indicating that this finding is specific to the circular forms. In addition, the high circPSEN1 levels do not seem to be specific to PSEN1 mutation carriers; the counts are also elevated in APP and PSEN2 mutation carriers. In-silico functional analyses suggest that circPSEN1 is involved in several pathways such as axon guidance (p=3.39×10−07), hippo signaling pathway (p=7.38×10−07), lysine degradation (p=2.48×10−05) or Wnt signaling pathway (p=5.58×10−04) among other KEGG pathways. Additionally, circPSEN1 counts were able to discriminate ADAD from sporadic AD and controls with an AUC above 0.70.ConclusionsOur findings show the differential expression of circPSEN1 is increased in ADAD. Given the biological function previously ascribed to circular RNAs and the results of our in-silico analyses, we hypothesize that this finding might be related to neuroinflammatory events that lead or that are caused by the accumulation of amyloid-beta.

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Section: -Discussionmentioning

confidence: 95%

Circular RNA detection identifiescircPSEN1alterations in brain specific to Autosomal Dominant Alzheimer Disease

Chen

Eteleeb

Wang

et al. 2021

Preprint

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“…Pathway analysis of hippocampal volume‐related and WMH‐related proteins revealed five and six significantly enriched pathways, respectively. Some of them have been reported being associated with AD such as axon guidance, 60 MAPK signaling pathway, 61 and cell adhesion molecules (CAMs), 62 further demonstrating the relatedness of these proteins with AD. Furthermore, most neurodegeneration and vascular damage‐related proteins and protein modules were associated with cognitive score and their direction of association were in concordance with brain MRI correlations.…”

Section: Discussionmentioning

confidence: 98%

Identification of plasma proteins relating to brain neurodegeneration and vascular pathology in cognitively normal individuals

Shi

Buchanan

Cox

et al. 2021

Alz & Dem Diag Ass & Dis Mo

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Introduction:This study aims to first discover plasma proteomic biomarkers relating to neurodegeneration (N) and vascular (V) damage in cognitively normal individuals and second to discover proteins mediating sex-related difference in N and V pathology.Methods: Five thousand and thirty-two plasma proteins were measured in 1061 cognitively normal individuals (628 females and 433 males), nearly 90% of whom had magnetic resonance imaging measures of hippocampal volume (as N) and white matter hyperintensities (as V).

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“…KEGG analysis has enriched the regulatory network of multiple signaling pathways in POD progression, and many signaling pathways have been fully validated in AD models. For example, axon-guiding molecules play a role in the occurrence and development of AD by participating in different mechanisms ( Zhang et al, 2021 ). Dysregulation of UPP (ubiquitin–proteasome pathway) protein degradation contributes to cognitive impairment in aging and AD ( Hegde et al, 2019 ), and in particular, the local regulation of ligases in neurons may be important ( Hegde and Upadhya, 2007 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of Potential Key circRNAs in Aged Mice With Postoperative Delirium

Wei

Liang

Yuan

et al. 2022

Front. Mol. Neurosci.

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Postoperative delirium (POD) is a common postoperative complication in elderly patients and seriously affects postoperative recovery. The exact mechanism of POD is still unclear. Therefore, it is necessary to explore the mechanism of POD in transcriptional regulation. At present, circRNAs have been proven to play an important role in a variety of mental health and cognitive disorders, such as Alzheimer’s disease, depression and schizophrenia. To reveal the effect of circRNA on POD, we used microarray to analyze the differential expression profiles of circRNAs in the hippocampus of 12-month-old mice between the tibial fracture and control groups. A total of 1,4236 circRNAs were identified. Compared with the control group, there were 500 circRNAs with increased expression and 187 with decreased expression. The accuracy of the microarray data was further verified by qRT–PCR. Finally, GO enrichment and KEGG pathway analyses indicated that changes in axon orientation, ubiquitin-mediated proteolysis, glutamate synapses, the estrogen signaling pathway, the RAS signaling pathway and other systems may be important potential pathological mechanisms in the progression of POD. In particular, we found that the HOMER1 gene and its transcript mmu_circRNA_26701 are specifically expressed in the glutamate synapse, which may provide new clues and intervention targets for the progression of this refractory disease.

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Roles and Mechanisms of Axon-Guidance Molecules in Alzheimer’s Disease

Cited by 37 publications

References 175 publications

Circular RNA detection identifiescircPSEN1alterations in brain specific to Autosomal Dominant Alzheimer Disease

Circular RNA detection identifiescircPSEN1alterations in brain specific to Autosomal Dominant Alzheimer Disease

Identification of plasma proteins relating to brain neurodegeneration and vascular pathology in cognitively normal individuals

Identification of Potential Key circRNAs in Aged Mice With Postoperative Delirium

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