Role of Semaphorins in Ischemic Stroke

Du, Huaping; Xu, Yuan; Zhu, Li

doi:10.3389/fnmol.2022.848506

Cited by 10 publications

(3 citation statements)

References 165 publications

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“…For example, SEMA4D, a member of the semaphorin family, is upregulated in the neurovascular unit after ischemic stroke, where it exerts multiple neuroprotective effects. 68,69 Moreover, this gene has been additionally highlighted in our protein-protein interaction analysis as strongly associated with known AD genes. Another example is SPRY2, which was highlighted in our analyses as a suggestive gene for VaD and had strong functional associations with known ADRD genes.…”

Section: Discussionmentioning

confidence: 86%

A meta-analysis of genome-wide association studies identifies new genetic loci associated with all-cause and vascular dementia

Fongang

Sargurupremraj²,

Jian³

et al. 2022

Preprint

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Dementia is multifactorial with Alzheimer (AD) and vascular (VaD) pathologies making the largest contributions. Genome-wide association studies (GWAS) have identified over 70 genetic risk loci for AD but the genomic determinants of other dementias, including VaD remain understudied. We hypothesize that common forms of dementia will share genetic risk factors and conducted the largest GWAS to date of "all-cause dementia" (ACD) and examined the genetic overlap with VaD. Our dataset includes 809,299 individuals from European, African, Asian, and Hispanic ancestries with 46,902 and 8,702 cases of ACD and VaD, respectively. We replicated known AD loci at genome-wide significance for both ACD and VaD and conducted bioinformatic analyses in prioritizing genes that are functionally relevant and shared with closely related traits and risk factors. For ACD, novel loci were associated with energy transport throughout the brain (SEMA4D), neuronal excitability (ANO3), amyloid plaques deposition in the brain (RBFOX1), and MRI markers of small vessel disease (HBEGF). Novel VaD loci were associated with hypertension, diabetes, and neuron maintenance (SPRY2, FOXA2, AJAP1, and PSMA3). In addition to the genetic overlap with neurodegenerative processes, genetic risk loci for ACD exhibited overlap with vascular risk factors (Type-II diabetes, blood pressure, lipid levels) and MRI markers of cerebral small vessel disease (cSVD). Our study identified genetic risk loci underlying ACD and VaD that point to the involvement of specific biological pathways and highlights their genetic overlap with vascular risk factors and MRI markers of cSVD. These novel insights could lead to new prevention and treatment strategies.

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Section: Discussionmentioning

confidence: 86%

A meta-analysis of genome-wide association studies identifies new genetic loci associated with all-cause and vascular dementia

Fongang

Sargurupremraj²,

Jian³

et al. 2022

Preprint

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“…The NVU comprises neurons, glial cells, endothelial cells, smooth muscle cells, pericytes, and an extracellular matrix. Its integrity is crucial for maintaining homeostasis within the brain microenvironment, regulating cerebral blood flow, and promoting neuro repair during AIS [ 168 - 170 ]. TFEB is highly expressed in the CNS and is crucially involved in maintaining the integrity of the NVU.…”

Section: Tfeb Regulates Pathophysiological Processes In Ischemic Strokementioning

confidence: 99%

Transcription Factor EB: A Promising Therapeutic Target for Ischemic Stroke

Shao

Lang

Ding

et al. 2024

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Transcription factor EB (TFEB) is an important endogenous defensive protein that responds to ischemic stimuli. Acute ischemic stroke is a growing concern due to its high morbidity and mortality. Most survivors suffer from disabilities such as numbness or weakness in an arm or leg, facial droop, difficulty speaking or understanding speech, confusion, impaired balance or coordination, or loss of vision. Although TFEB plays a neuroprotective role, its potential effect on ischemic stroke remains unclear. This article describes the basic structure, regulation of transcriptional activity, and biological roles of TFEB relevant to ischemic stroke. Additionally, we explore the effects of TFEB on the various pathological processes underlying ischemic stroke and current therapeutic approaches. The information compiled here may inform clinical and basic studies on TFEB, which may be an effective therapeutic drug target for ischemic stroke.

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“…Both neuronal and non-neuronal cells in brain express Sema 3A, including microglia cells, astrocytes, endothelial cells and oligodendrocytes. Sema 3A expression is high during the early stages of embryonic development, but it reaches a peak only around the first postnatal week [9,10]. Later, after birth, Sema 3A levels decline, although in adulthood its expression still persists in brain areas that retain plasticity and/or neurogenesis, such as the olfactory bulb, hippocampus, and cerebellum [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

An increase in Semaphorin 3A biases the axonal direction and induces an aberrant dendritic arborization in an in vitro model of human neural progenitor differentiation

et al. 2022

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Background Semaphorins (Sema) belong to a large family of repellent guidance cues instrumental in guiding axons during development. In particular, Class 3 Sema (Sema 3) is among the best characterized Sema family members and the only produced as secreted proteins in mammals, thereby exerting both autocrine and paracrine functions. Intriguingly, an increasing number of studies supports the crucial role of the Sema 3A in hippocampal and cortical neurodevelopment. This means that alterations in Sema 3A signaling might compromise hippocampal and cortical circuits and predispose to disorders such as autism and schizophrenia. Consistently, increased Sema 3A levels have been detected in brain of patients with schizophrenia and many polymorphisms in Sema 3A or in the Sema 3A receptors, Neuropilins (Npn 1 and 2) and Plexin As (Plxn As), have been associated to autism. Results Here we present data indicating that when overexpressed, Sema 3A causes human neural progenitors (NP) axonal retraction and an aberrant dendritic arborization. Similarly, Sema 3A, when overexpressed in human microglia, triggers proinflammatory processes that are highly detrimental to themselves as well as NP. Indeed, NP incubated in microglia overexpressing Sema 3A media retract axons within an hour and then start suffering and finally die. Sema 3A mediated retraction appears to be related to its binding to Npn 1 and Plxn A2 receptors, thus activating the downstream Fyn tyrosine kinase pathway that promotes the threonine-serine kinase cyclin-dependent kinase 5, CDK5, phosphorylation at the Tyr15 residue and the CDK5 processing to generate the active fragment p35. Conclusions All together this study identifies Sema 3A as a critical regulator of human NP differentiation. This may imply that an insult due to Sema 3A overexpression during the early phases of neuronal development might compromise neuronal organization and connectivity and make neurons perhaps more vulnerable to other insults across their lifespan.

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Role of Semaphorins in Ischemic Stroke

Cited by 10 publications

References 165 publications

A meta-analysis of genome-wide association studies identifies new genetic loci associated with all-cause and vascular dementia

A meta-analysis of genome-wide association studies identifies new genetic loci associated with all-cause and vascular dementia

Transcription Factor EB: A Promising Therapeutic Target for Ischemic Stroke

An increase in Semaphorin 3A biases the axonal direction and induces an aberrant dendritic arborization in an in vitro model of human neural progenitor differentiation

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