Chronic cerebral hypoperfusion-induced impairment of Aβ clearance requires HB-EGF-dependent sequential activation of HIF1α and MMP9

Ashok, Anushruti; Kumar, Narendra; Raza, Waseem; Pandey, Rukmani; Bandyopadhyay, Sanghamitra

doi:10.1016/j.nbd.2016.07.013

Cited by 56 publications

(41 citation statements)

References 57 publications

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“…Furthermore, the glymphatic system has recently been characterized as an additional potential therapeutic target [88]. This hypothesis is supported by a study using aquaporin-4 knockout (AQP4 −/− ) mice with hemorrhagic stroke, which showed significantly more gliosis, more severe neuroinflammatory patterns, and worse neurological outcome [130] Liu et al [82] Zlokovic et al [60] Post-stroke Aβ accumulation leads to inflammatory processes and neurodegeneration, typical in dementia Zlokovic [131] Kinnecom et al [132] Zlokovic et al [60,129] Lack of Aβ-RAGE complexes after stroke leads to a pro-inflammatory cascade and Aβ accumulation, which can contribute to neurotoxicity Deane et al [61] Liu et al [62] Correlation between Aβ deposits and sleep disorder is a common risk factor for stroke and AD Holth et al [95] Ma et al [96] Joa et al [97] CSF clearance and the glymphatic system are impaired with both stroke and AD, leading to accumulation of waste metabolites in the brain Silverberg et al [145] Weller et al [16] Weller et al [6] Kress et al [14] Gaberel et al [17] Peng et al [15] Goulay et al [18] Lundgaard et al [90] Borwn et al [19] CAA and AD are associated with modifications in perivascular spaces, which can lead to flow disturbance, stroke, and Aβ accumulation…”

Section: Treatment Strategiesmentioning

confidence: 88%

“…Furthermore, impaired LRP-1-mediated transcytosis across the BBB may lead to insufficient clearance of Aβ protein. Impaired LRP-1 and RAGE efficiency may also be due to hypoperfusion or hypoxia, which increase heparin-binding EGF-like growth factor (HB-EGF) mRNA [130]. Oxidated LRP-1 is no longer able to trap the Aβ protein from the parenchyma to release it in the intraluminal part of the vessels.…”

Section: Vascular Impairmentmentioning

confidence: 99%

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From Stroke to Dementia: a Comprehensive Review Exposing Tight Interactions Between Stroke and Amyloid-β Formation

Goulay

Romo

Hol

et al. 2019

Transl. Stroke Res.

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Stroke and Alzheimer's disease (AD) are cerebral pathologies with high socioeconomic impact that can occur together and mutually interact. Vascular factors predisposing to cerebrovascular disease have also been specifically associated with development of AD, and acute stroke is known to increase the risk to develop dementia. Despite the apparent association, it remains unknown how acute cerebrovascular disease and development of AD are precisely linked and act on each other. It has been suggested that this interaction is strongly related to vascular deposition of amyloid-β (Aβ), i.e., cerebral amyloid angiopathy (CAA). Furthermore, the blood-brain barrier (BBB), perivascular space, and the glymphatic system, the latter proposedly responsible for the drainage of solutes from the brain parenchyma, may represent key pathophysiological pathways linking stroke, Aβ deposition, and dementia. In this review, we propose a hypothetic connection between CAA, stroke, perivascular space integrity, and dementia. Based on relevant pre-clinical research and a few clinical case reports, we speculate that impaired perivascular space integrity, inflammation, hypoxia, and BBB breakdown after stroke can lead to accelerated deposition of Aβ within brain parenchyma and cerebral vessel walls or exacerbation of CAA. The deposition of Aβ in the parenchyma would then be the initiating event leading to synaptic dysfunction, inducing cognitive decline and dementia. Maintaining the clearance of Aβ after stroke could offer a new therapeutic approach to prevent post-stroke cognitive impairment and development into dementia.

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Section: Treatment Strategiesmentioning

confidence: 88%

Section: Vascular Impairmentmentioning

confidence: 99%

From Stroke to Dementia: a Comprehensive Review Exposing Tight Interactions Between Stroke and Amyloid-β Formation

Goulay

Romo

Hol

et al. 2019

Transl. Stroke Res.

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“…Fluorescence immunoreactivity was quantified using an RGB plugin of the Image‐J 1.43q software (http://rsb.info.nih.gov/ij/; developed by Wayne Rasband, National Institutes of Health, Bethesda, MD, USA) as described earlier (Jensen ; Ashok et al . ).…”

Section: Methodsmentioning

confidence: 97%

Docosahexaenoic acid up‐regulates both PI3K/AKT‐dependent FABP7–PPARγ interaction and MKP3 that enhance GFAP in developing rat brain astrocytes

Tripathi

Kushwaha

Mishra

et al. 2016

Journal of Neurochemistry

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The astrocyte marker, glial fibrillary acidic protein (GFAP), has essential functions in the brain, but may trigger astroglial scarring when expressed in excess. Docosahexaenoic acid (DHA) is an n-3 fatty acid that is protective during brain development. However, the effect of DHA on GFAP levels of developing brain remains unexplored. Here, we detected that treating developing rats with DHA-enriched fish-oil caused dose-dependent GFAP augmentation. We investigated the mechanism promoting GFAP, hypothesizing the participation of fatty acid-binding protein-7 (FABP7), known to bind DHA.We identified that DHA stimulated FABP7 expression in astrocytes, and FABP7-silencing suppressed DHA-induced GFAP, indicating FABP7-mediated GFAP increase. Further investigation proved FABP7 expression to be phosphatidylinositide 3-kinases (PI3K)/AKT and nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARc)-dependent. We found that PI3K/AKT activated PPARc that triggered FABP7 expression via PPARc-responsive elements within its gene. Towards identifying FABP7-downstream pathways, we considered our previous report that demonstrated cyclin-dependent kinase-5 (CDK5)-PPARc-protein-protein Abbreviations used: BBB, blood-brain barrier; CDK5, cyclindependent kinase-5; CNS, central nervous system; DHA, docosahexaenoic acid; FABP7, fatty acid-binding protein-7; GFAP, glial fibrillary acidic protein; MKP3, MAP-kinase-phosphatase-3; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PPARc, peroxisome proliferatoractivated receptor-gamma. 96© complex to suppress GFAP. We found that the DHA-induced FABP7 underwent protein-protein interaction with PPARc, which impeded CDK5-PPARc formation. Hence, it appeared that enhanced FABP7-PPARc in lieu of CDK5-PPARc resulted in increased GFAP. PI3K/AKT not only stimulated formation of FABP7-PPARc protein-protein complex, but also up-regulated a FABP7-independent MAP-kinase-phosphatase-3 pathway that inactivated CDK5 and hence attenuated CDK5-PPARc. Overall, our data reveal that via the proximal PI3K/AKT, DHA induces FABP7-PPARc, through genomic and non-genomic mechanisms, and MAP-kinase-phosphatase-3 that converged at attenuated CDK5-PPARc and therefore, enhanced GFAP. Accordingly, our study demonstrates a DHA-mediated astroglial hyperactivation, pointing toward a probable injurious role of DHA in brain development.

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“…PRUNE2 is a gene associated with response to amphetamine [48] and hippocampal atrophy which is a quantitative trait for AD [49]. HBEGF is associated with AD in APOE ε 4population [50] and involved in Aβ clearance [51]. PROK2 is a gene involved in Aβ-induced neurotoxicity [52].…”

Section: Identify Shared Genetic Components Between Ad and Pdmentioning

confidence: 99%

Systematic tissue-specific functional annotation of the human genome highlights immune-related DNA elements for late-onset Alzheimer’s disease

Powles

Abdallah

et al. 2016

Preprint

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Continuing efforts from large international consortia have made genome-wide epigenomic and transcriptomic annotation data publicly available for a variety of cell and tissue types. However, synthesis of these datasets into effective summary metrics to characterize the functional noncoding genome remains a challenge. Here, we present GenoSkyline-Plus, an extension of our previous work through integration of an expanded set of epigenomic and transcriptomic annotations to produce high-resolution, single tissue annotations. After validating our annotations with a catalog of tissue-specific non-coding elements previously identified in the literature, we apply our method using data from 127 different cell and tissue types to present an atlas of heritability enrichment across 45 different GWAS traits. We show that broader organ system categories (e.g. immune system) increase statistical power in identifying biologically relevant tissue types for complex diseases while annotations of individual cell types (e.g. CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under aThe copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/078865 doi: bioRxiv preprint first posted online Oct. 2, 2016; Author SummaryAfter years of community efforts, many experimental and computational approaches have been developed and applied for functional annotation of the human genome, yet proper annotation still remains challenging, especially in non-coding regions. As complex disease research rapidly advances, increasing evidence suggests that non-coding regulatory DNA elements may be the primary regions harboring risk variants in human complex diseases. In this paper, we introduce GenoSkyline-Plus, a principled annotation framework to identify tissue and cell type-specific functional regions in the human genome through integration of diverse high-throughput epigenomic and transcriptomic data. Through validation of known non-coding tissue-specific regulatory regions, enrichment analyses on 45 complex traits, and an in-depth case study of neurodegenerative diseases, we demonstrate the ability of GenoSkyline-Plus to accurately identify tissue-specific functionality in the human genome and provide unbiased, genome-wide insights into the genetic basis of human complex diseases.

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Chronic cerebral hypoperfusion-induced impairment of Aβ clearance requires HB-EGF-dependent sequential activation of HIF1α and MMP9

Cited by 56 publications

References 57 publications

From Stroke to Dementia: a Comprehensive Review Exposing Tight Interactions Between Stroke and Amyloid-β Formation

From Stroke to Dementia: a Comprehensive Review Exposing Tight Interactions Between Stroke and Amyloid-β Formation

Docosahexaenoic acid up‐regulates both PI3K/AKT‐dependent FABP7–PPARγ interaction and MKP3 that enhance GFAP in developing rat brain astrocytes

Systematic tissue-specific functional annotation of the human genome highlights immune-related DNA elements for late-onset Alzheimer’s disease

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