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They found that CSF soluble platelet-derived growth factor receptor-beta increased with higher CDR scores, suggesting progressive pericyte damage with cognitive dysfunction. Higher soluble platelet-derived growth factor receptor-beta remained a significant predictor of cognitive impairment even after controlling for amyloid-beta or tau.
In a subset of 73 patients who had gadolinium-based contrast MRI, soluble platelet-derived growth factor receptor-beta was positively correlated with blood-brain barrier breakdown, limited to the hippocampus and medial temporal lobe structures.
"These brain regions show the earliest pathology in Alzheimer's disease and are associated with memory deficits," observed Gwenn Smith, PhD, of Johns Hopkins School of Medicine, who was not part of the research. "These promising results support further investigation of CSF and MRI measures of blood-brain barrier breakdown as an early pathological event associated with the development of Alzheimer's disease," she told MedPage Today.
Neurosci Lett. 2015 Oct 21;607:97-101. doi: 10.1016/j.neulet.2015.09.025. Epub 2015 Sep 25.
Shedding of soluble platelet-derived growth factor receptor-ß from human brain pericytes.
Sagare AP1, Sweeney MD1, Makshanoff J1, Zlokovic BV2.
Author information
Abstract
Platelet-derived growth factor receptor-ß (PDGFRß) is expressed in the brain by vascular mural cells-brain capillary pericytes and arterial vascular smooth muscle cells (VSMCs). Recent evidence shows that blood-brain barrier (BBB) disruption and increased permeability, especially in the hippocampus, positively correlates with elevated levels of soluble PDGFRß (sPDGFRß) in cerebrospinal fluid (CSF) in patients with mild dementia. To determine which vascular cell type(s) contributes to increased sPDGFRß in CSF, we compared PDGFRß expression and sPDGFRß shedding in response to injury in early passage primary cultures of human brain pericytes, brain arterial VSMCs, and brain endothelial cells. PDGFRß protein was undetectable in endothelial cells, but was found both in pericytes and VSMCs. PDGFRß relative protein abundance was by 4.2-fold (p<0.05) higher in pericytes compared to VSMCs. Hypoxia (1% O2) or amyloid-ß peptide (25 µM) compared to normoxia (21% O2) both increased over 48 h shedding of sPDGFRß and its levels in the culture medium from pericytes cultures, but not from VSMCs cultures, by 4.3-fold and 4.6-fold, respectively, compared to the basal sPDGFRß levels in the medium (1.43±0.15 ng/ml). This was associated with the corresponding loss of cell-associated PDGFRß from pericytes and no change in cellular levels of PDGFRß in VSMCs. Thus, sPDGFRß is a biomarker of pericyte injury, and elevated sPDGFRß levels in biofluids in patients with dementia and/or other neurodegenerative disorders likely reflects pericyte injury, which supports the potential for sPDGFRß to be developed and validated as a biomarker of brain pericyte injury and BBB dysfunction.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
KEYWORDS:
Role of platelet-derived growth factors in physiology and medicine
Johanna Andrae1,2, Radiosa Gallini1, and Christer Betsholtz1,2,3,4
+ Author Affiliations
1 Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE 171 77 Stockholm, Sweden;
2 Ludwig Institute for Cancer Research, Stockholm Branch, Karolinska Institutet, SE 171 77 Stockholm, Sweden;
3 Department of Medicine, Karolinska Institutet, SE 171 77 Stockholm, Sweden
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Abstract
Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) have served as prototypes for growth factor and receptor tyrosine kinase function for more than 25 years. Studies of PDGFs and PDGFRs in animal development have revealed roles for PDGFR-a signaling in gastrulation and in the development of the cranial and cardiac neural crest, gonads, lung, intestine, skin, CNS, and skeleton. Similarly, roles for PDGFR-ß signaling have been established in blood vessel formation and early hematopoiesis. PDGF signaling is implicated in a range of diseases. Autocrine activation of PDGF signaling pathways is involved in certain gliomas, sarcomas, and leukemias. Paracrine PDGF signaling is commonly observed in epithelial cancers, where it triggers stromal recruitment and may be involved in epithelial–mesenchymal transition, thereby affecting tumor growth, angiogenesis, invasion, and metastasis. PDGFs drive pathological mesenchymal responses in vascular disorders such as atherosclerosis, restenosis, pulmonary hypertension, and retinal diseases, as well as in fibrotic diseases, including pulmonary fibrosis, liver cirrhosis, scleroderma, glomerulosclerosis, and cardiac fibrosis. We review basic aspects of the PDGF ligands and receptors, their developmental and pathological functions, principles of their pharmacological inhibition, and results using PDGF pathway-inhibitory or stimulatory drugs in preclinical and clinical contexts.
Keywords
PDGF receptor cancer development fibrosis platelet-derived growth factor
Platelet-derived growth factor (PDGF) was identified more than three decades ago as a serum growth factor for fibroblasts, smooth muscle cells (SMCs), and glia cells (Kohler and Lipton 1974; Ross et al. 1974; Westermark and Wasteson 1976). Human PDGF was originally identified as a disulfide-linked dimer of two different polypeptide chains, A and B, separable using reversed phase chromatography (Johnsson et al. 1982). The B-chain (PDGF-B) was characterized by amino acid sequencing, revealing a close homology between PDGF-B and the product of the retroviral oncogene v-sis of simian sarcoma virus (SSV) (Doolittle et al. 1983; Waterfield et al. 1983). Subsequent studies confirmed that the human cellular counterpart (c-sis) was identical to PDGF-B and that autocrine PDGF activity was sufficient for SSV transformation in vitro. This was a paradigm-shifting discovery about the relationship between neoplastic cell transformation and normal growth control. For the first time, the importance of autocrine growth stimulation in neoplastic transformation was demonstrated. As discussed below, it is now well established that autocrine PDGF stimulation plays a role also in some human cancers.
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