VEGFR1 and VEGFR2 in Alzheimer’s Disease

Harris, Rachel; Miners, Scott; Allen, Shelley J; Love, Seth

doi:10.3233/jad-170745

Cited by 55 publications

(45 citation statements)

References 80 publications

(114 reference statements)

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“…It has been shown that VEGF-α, a potent angiogenic factor, is upregulated in the AD brain, speculated to be a secondary response to Aβ-induced vascular injuries in the brain [64]. Our findings, however, suggest an alternative possibility.…”

Section: Int J Mol Sci 2019 20 X For Peer Reviewmentioning

confidence: 57%

Dysregulated Gut Homeostasis Observed Prior to the Accumulation of the Brain Amyloid-β in Tg2576 Mice

Honarpisheh

Reynolds

Conesa

et al. 2020

IJMS

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Amyloid plaques in Alzheimer’s disease (AD) are associated with inflammation. Recent studies demonstrated the involvement of the gut in cerebral amyloid-beta (Aβ) pathogenesis; however, the mechanisms are still not well understood. We hypothesize that the gut bears the Aβ burden prior to brain, highlighting gut–brain axis (GBA) interaction in neurodegenerative disorders. We used pre-symptomatic (6-months) and symptomatic (15-months) Tg2576 mouse model of AD compared to their age-matched littermate WT control. We identified that dysfunction of intestinal epithelial barrier (IEB), dysregulation of absorption, and vascular Aβ deposition in the IEB occur before cerebral Aβ aggregation is detectible. These changes in the GBA were associated with elevated inflammatory plasma cytokines including IL-9, VEGF and IP-10. In association with reduced cerebral myelin tight junction proteins, we identified reduced levels of systemic vitamin B12 and decrease cubilin, an intestinal B12 transporter, after the development of cerebral Aβ pathology. Lastly, we report Aβ deposition in the intestinal autopsy from AD patients with confirmed cerebral Aβ pathology that is not present in intestine from non-AD controls. Our data provide evidence that gut dysfunction occurs in AD and may contribute to its etiology. Future therapeutic strategies to reverse AD pathology may involve the early manipulation of gut physiology and its microbiota.

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Section: Int J Mol Sci 2019 20 X For Peer Reviewmentioning

confidence: 57%

Dysregulated Gut Homeostasis Observed Prior to the Accumulation of the Brain Amyloid-β in Tg2576 Mice

Honarpisheh

Reynolds

Conesa

et al. 2020

IJMS

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“…However, increased levels of VEGF and VEGFR2, the receptor for VEGF at the site of inflammation, can cause increased BBB permeability, edema in neuroinflammatory conditions including neurotrauma, and brain microvascular endothelial activation [61,62]. VEGFR2 is known to be expressed by neurons, glia, and endothelial cells in the brain [63]. Brain injury induces angiogenesis in the brain.…”

Section: Mediators Of Inflammationmentioning

confidence: 99%

Mast Cell Activation, Neuroinflammation, and Tight Junction Protein Derangement in Acute Traumatic Brain Injury

Kempuraj

Ahmed

Selvakumar

et al. 2020

Mediators of Inflammation

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Traumatic brain injury (TBI) is one of the major health problems worldwide that causes death or permanent disability through primary and secondary damages in the brain. TBI causes primary brain damage and activates glial cells and immune and inflammatory cells, including mast cells in the brain associated with neuroinflammatory responses that cause secondary brain damage. Though the survival rate and the neurological deficiencies have shown significant improvement in many TBI patients with newer therapeutic options, the underlying pathophysiology of TBI-mediated neuroinflammation, neurodegeneration, and cognitive dysfunctions is understudied. In this study, we analyzed mast cells and neuroinflammation in weight drop-induced TBI. We analyzed mast cell activation by toluidine blue staining, serum chemokine C-C motif ligand 2 (CCL2) level by enzyme-linked immunosorbent assay (ELISA), and proteinase-activated receptor-2 (PAR-2), a mast cell and inflammation-associated protein, vascular endothelial growth factor receptor 2 (VEGFR2), and blood-brain barrier tight junction-associated claudin 5 and Zonula occludens-1 (ZO-1) protein expression in the brains of TBI mice. Mast cell activation and its numbers increased in the brains of 24 h and 72 h TBI when compared with sham control brains without TBI. Mouse brains after TBI show increased CCL2, PAR-2, and VEGFR2 expression and derangement of claudin 5 and ZO-1 expression as compared with sham control brains. TBI can cause mast cell activation, neuroinflammation, and derangement of tight junction proteins associated with increased BBB permeability. We suggest that inhibition of mast cell activation can suppress neuroimmune responses and glial cell activation-associated neuroinflammation and neurodegeneration in TBI.

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“…The neurotrophic and neuroprotective effects of VEGF are predominantly mediated by VEGFR2, also called fetal Flk-1 [ 14 , 57 , 58 , 59 ], or kinase insert-domain containing receptor (KDR) [ 60 ]. VEGF/VEGFR2 (Flk-1) signaling may have neuroprotective effects in many neurological diseases, such as hemorrhagic or ischemic stroke [ 16 , 17 , 18 ], traumatic brain injury [ 61 ], amyotrophic lateral sclerosis [ 20 ], Huntington’s disease [ 62 ], Alzheimer’s disease [ 12 , 21 ], and Parkinson’s disease [ 12 , 22 ]. Recent evidence showed that during status epilepticus, VEGF is upregulated and it protects against seizure-induced neuronal cell death in the hippocampus [ 14 , 19 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…Under perturbations of neuronal cells, availability of VEGFA to bind to VGEFR2 (Flk-1) will increase and promote VGEFR2 (Flk-1) downstream signaling [ 9 , 12 , 14 ]. Recent evidence suggests that VEGF has therapeutic potential as a neuroprotective factor in many neurological diseases [ 12 , 15 ], such as stroke [ 16 , 17 , 18 ], epilepsy [ 14 , 19 ], and neurodegenerative diseases [ 12 , 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor γ Coactivator 1α Activates Vascular Endothelial Growth Factor That Protects Against Neuronal Cell Death Following Status Epilepticus through PI3K/AKT and MEK/ERK Signaling

Huang

Hsu

Pan

et al. 2020

IJMS

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Status epilepticus may cause molecular and cellular events, leading to hippocampal neuronal cell death. Peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) is an important regulator of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2), also known as fetal liver kinase receptor 1 (Flk-1). Resveratrol is an activator of PGC-1α. It has been suggested to provide neuroprotective effects in epilepsy, stroke, and neurodegenerative diseases. In the present study, we used microinjection of kainic acid into the left hippocampal CA3 region in Sprague Dawley rats to induce bilateral prolonged seizure activity. Upregulating the PGC-1α pathway will increase VEGF/VEGFR2 (Flk-1) signaling and further activate some survival signaling that includes the mitogen activated protein kinase kinase (MEK)/mitogen activated protein kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways and offer neuroprotection as a consequence of apoptosis in the hippocampal neurons following status epilepticus. Otherwise, downregulation of PGC-1α by siRNA against pgc-1α will inhibit VEGF/VEGFR2 (Flk-1) signaling and suppress pro-survival PI3K/AKT and MEK/ERK pathways that are also accompanied by hippocampal CA3 neuronal cell apoptosis. These results may indicate that the PGC-1α induced VEGF/VEGFR2 pathway may trigger the neuronal survival signaling, and the PI3K/AKT and MEK/ERK signaling pathways. Thus, the axis of PGC-1α/VEGF/VEGFR2 (Flk-1) and the triggering of downstream PI3K/AKT and MEK/ERK signaling could be considered an endogenous neuroprotective effect against apoptosis in the hippocampus following status epilepticus.

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VEGFR1 and VEGFR2 in Alzheimer’s Disease

Cited by 55 publications

References 80 publications

Dysregulated Gut Homeostasis Observed Prior to the Accumulation of the Brain Amyloid-β in Tg2576 Mice

Dysregulated Gut Homeostasis Observed Prior to the Accumulation of the Brain Amyloid-β in Tg2576 Mice

Mast Cell Activation, Neuroinflammation, and Tight Junction Protein Derangement in Acute Traumatic Brain Injury

Peroxisome Proliferator-Activated Receptor γ Coactivator 1α Activates Vascular Endothelial Growth Factor That Protects Against Neuronal Cell Death Following Status Epilepticus through PI3K/AKT and MEK/ERK Signaling

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