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ABSTRACT: Angiogenesis has not been extensively studied in Parkinson’s disease (PD) despite being associated with other neurodegenerative
disorders. Post-mortem human brain tissues were obtained from subjects with pathologically confirmed Parkinson’s disease (PD)
and progressive supranuclear palsy (PSP), a rapidly progressing Parkinsonian-like disorder. Tissues were also obtained from
subjects with incidental Lewy body disease (iLBD) who had Lewy bodies in the substantia nigra pars compacta (SNpc) but had not been diagnosed with PD, and age-matched controls without Lewy body pathology. The SNpc, putamen, locus ceruleus
(LC) and midfrontal cortex were examined for integrin αvβ3, a marker for angiogenesis, along with vessel number and activated
microglia. All parkinsonian syndromes had greater αvβ3 in the LC and the SNpc, while only PD and PSP subjects had elevated αvβ3 in the putamen compared to controls. PD and PSP subjects also had increases
in microglia number and activation in the SNpc suggesting a link between inflammation and clinical disease. Microglia activation in iLBD subjects was limited to the LC,
an area involved at an early stage of PD. Likewise, iLBD subjects did not differ from controls in αvβ3 staining in the putamen,
a late area of involvement in PD. The presence of αvβ3 reactive vessels in PD and its syndromes is indicative of newly created
vessels that have not likely developed the restrictive properties of the blood brain barrier. Such angiogenic vessels could
contribute to neuroinflammation by failing to protect the parenchyma from peripheral immune cells and inflammatory or toxic
factors in the peripheral circulation.
KeywordsAngiogenesis–Parkinson’s disease–Incidental Lewy body disease–Progressive supranuclear palsy–Integrin αvβ3–Microglia
Acta Neurovegetativa 04/2012; 119(1):59-71. · 2.73 Impact Factor
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ABSTRACT: Angiogenesis has not been extensively studied in Parkinson's disease (PD) despite being associated with other neurodegenerative disorders. Post-mortem human brain tissues were obtained from subjects with pathologically confirmed Parkinson's disease (PD) and progressive supranuclear palsy (PSP), a rapidly progressing Parkinsonian-like disorder. Tissues were also obtained from subjects with incidental Lewy body disease (iLBD) who had Lewy bodies in the substantia nigra pars compacta (SN(pc)) but had not been diagnosed with PD, and age-matched controls without Lewy body pathology. The SNpc, putamen, locus ceruleus (LC) and midfrontal cortex were examined for integrin αvβ3, a marker for angiogenesis, along with vessel number and activated microglia. All parkinsonian syndromes had greater αvβ3 in the LC and the SN(pc), while only PD and PSP subjects had elevated αvβ3 in the putamen compared to controls. PD and PSP subjects also had increases in microglia number and activation in the SN(pc) suggesting a link between inflammation and clinical disease. Microglia activation in iLBD subjects was limited to the LC, an area involved at an early stage of PD. Likewise, iLBD subjects did not differ from controls in αvβ3 staining in the putamen, a late area of involvement in PD. The presence of αvβ3 reactive vessels in PD and its syndromes is indicative of newly created vessels that have not likely developed the restrictive properties of the blood brain barrier. Such angiogenic vessels could contribute to neuroinflammation by failing to protect the parenchyma from peripheral immune cells and inflammatory or toxic factors in the peripheral circulation.
Acta Neurovegetativa 07/2011; 119(1):59-71. · 2.73 Impact Factor
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ABSTRACT: We previously demonstrated that several dopamine (DA) neurotoxins produced punctate areas of FITC-labeled albumin (FITC-LA) leakage in the substantia nigra and striatum suggesting blood brain barrier (BBB) dysfunction. Further, this leakage was co-localized with αvβ3 integrin up-regulation, a marker for angiogenesis. This suggested that the FITC-LA leakage might have been a result of angiogenesis. To assess the possible role of angiogenesis in DA neuron loss, we treated mice with 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) and on the following day treated with cyRGDfV, a cyclic peptide that binds to integrin αvβ3 and prevents angiogenesis. Post-treatment for 3 days (b.i.d.) with cyRGDfV blocked the MPTP-induced upregulation of integrin β3 immunoreactivity (a marker for angiogenesis), leakage of FITC-LA into brain parenchyma (a marker for BBB disruption) as well as the down regulation of Zona Occludin-1 (ZO-1; a marker for tight junction integrity). In addition, cyRGDfV also completely prevented tyrosine hydroxylase immunoreactive cell loss (a marker for DA neurons) and markedly attenuated the up-regulation of activated microglia (Iba1 cell counts and morphology). These data suggest that cyRGDfV, and perhaps other anti-angiogenic drugs, are neuroprotective following acute MPTP treatment and may suggest that compensatory angiogenesis and BBB dysfunction may contribute to inflammation and DA neuron loss.
Experimental Neurology 06/2011; 231(1):160-70. · 4.70 Impact Factor
