학술논문
Vascular endothelial growth factor isoforms differentially protect neurons against neurotoxic events associated with Alzheimer's disease.
Document Type
Academic Journal
Author
Alalwany RH; Tumour and Vascular Biology Laboratories, Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom.; Hawtrey T; School of Chemistry, University of New South Wales, Sydney, NSW, Australia.; Morgan K; School of Life Sciences, University of Nottingham, Nottingham, United Kingdom.; Morris JC; School of Chemistry, University of New South Wales, Sydney, NSW, Australia.; Donaldson LF; School of Life Sciences, University of Nottingham, Nottingham, United Kingdom.; Bates DO; Tumour and Vascular Biology Laboratories, Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom.; Pan African Cancer Research Institute, University of Pretoria, Pretoria, South Africa.
Source
Publisher: Frontiers Research Foundation Country of Publication: Switzerland NLM ID: 101477914 Publication Model: eCollection Cited Medium: Print ISSN: 1662-5099 (Print) Linking ISSN: 16625099 NLM ISO Abbreviation: Front Mol Neurosci Subsets: PubMed not MEDLINE
Subject
Language
English
ISSN
1662-5099
Abstract
Alzheimer's disease (AD) is the most common cause of dementia, the chronic and progressive deterioration of memory and cognitive abilities. AD can be pathologically characterised by neuritic plaques and neurofibrillary tangles, formed by the aberrant aggregation of β-amyloid and tau proteins, respectively. We tested the hypothesis that VEGF isoforms VEGF-A 165 a and VEGF-A 165 b, produced by differential splice site selection in exon 8, could differentially protect neurons from neurotoxicities induced by β-amyloid and tau proteins, and that controlling expression of splicing factor kinase activity could have protective effects on AD-related neurotoxicity in vitro . Using oxidative stress, β-amyloid, and tau hyperphosphorylation models, we investigated the effect of VEGF-A splicing isoforms, previously established to be neurotrophic agents, as well as small molecule kinase inhibitors, which selectively inhibit SRPK1, the major regulator of VEGF splicing. While both VEGF-A 165 a and VEGF-A 165 b isoforms were protective against AD-related neurotoxicity, measured by increased metabolic activity and neurite outgrowth, VEGF-A 165 a was able to enhance neurite outgrowth but VEGF-A 165 b did not. In contrast, VEGF-A 165 b was more effective than VEGF-A 165 a in preventing neurite "dieback" in a tau hyperphosphorylation model. SRPK1 inhibition was found to significantly protect against neurite "dieback" through shifting AS of VEGFA towards the VEGF-A 165 b isoform. These results indicate that controlling the activities of the two different isoforms could have therapeutic potential in Alzheimer's disease, but their effect may depend on the predominant mechanism of the neurotoxicity-tau or β-amyloid.
Competing Interests: LD, DB, and JM are founders and stock-holders in Exonate Ltd., a company that is developing SRPK1 inhibitors for clinical use. LD and JM are founders and stockholders in Emenda Therapeutics, a company that is developing splicing factor kinase inhibitors for therapeutic use. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Alalwany, Hawtrey, Morgan, Morris, Donaldson and Bates.)
Competing Interests: LD, DB, and JM are founders and stock-holders in Exonate Ltd., a company that is developing SRPK1 inhibitors for clinical use. LD and JM are founders and stockholders in Emenda Therapeutics, a company that is developing splicing factor kinase inhibitors for therapeutic use. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Alalwany, Hawtrey, Morgan, Morris, Donaldson and Bates.)