title: Decreased release of the angiogenic peptide vascular endothelial growth factor in Alzheimer's disease: recovering effect with insulin and DHEA sulfate.
abstract: Changes of vascular endothelial growth factor (VEGF) secretion have recently been demonstrated in patients with Alzheimer's disease (AD). Since VEGF has been involved in brain angiogenesis, neuroprotection and cerebromicrovascular exchange of substrates and nutrients, the study of VEGF could have important relapses into the pathogenesis and treatment of AD. Within this context, 35 healthy subjects (16 of young and 19 of old age), 18 patients with dementia of the vascular type (VAD) and 22 with dementia of the Alzheimer's type (AD) were included in the study. VEGF levels were determined in the supernates of circulating natural killer (NK) immune cells isolated by immunomagnetic separation (pure CD16 + CD56 + NK cells at a final density of 7.75 x 10(6) cells/ml). VEGF was measured in spontaneous conditions (without modulation) and after exposure of NK cells with IL-2, lipopolysaccharide (LPS), dehydroepiandrosterone sulfate (DHEAS), LPS + insulin, amyloid-beta (Abeta) fragment 1-42, the inactive sequence Abeta(40-1) and Abeta(1-42) + insulin. A significant decrease in VEGF released by NK cells was demonstrated in AD subjects compared to the other groups. No differences of VEGF levels were found between healthy subjects of old age and the VAD group. The incubation with LPS and DHEAS significantly increased, in a dose-dependent manner, VEGF levels in AD as well as in healthy subjects of young and old age and in VAD patients. The incubation of NK cells with Abeta(1-42) completely suppressed VEGF generation in AD subjects, also reducing VEGF release in the other groups. The co-incubation of NK with LPS + insulin, at different molar concentrations, significantly restored (4- and 6-fold increase from LPS alone) VEGF in AD, also enhancing VEGF secretion in healthy subjects and the VAD group, while the co-incubation of NK with Abeta(1-42) + insulin promptly abolished the negative effects of Abeta(1-42) on VEGF release. These data might suggest that the decreased VEGF secretion by peripheral immune cells of AD subjects could have a negative role for brain angiogenesis, neuroprotection and for brain microvascular permeability to nutrients, increasing brain frailty towards hypoxic injuries. On the contrary, insulin and DHEAS could have beneficial effects in AD, as well as in VAD and in physiological aging, by increasing, in a dose-dependent fashion, VEGF availability by peripheral and resident immune and endothelial cells, so contributing to increase its circulating pool.
authors.affiliation: Department of Internal Medicine and Geriatrics, University of Pavia, Pavia, Piazza Borromeo 2, IT-27100, Italy. brunos@unipv.it
authors.forename: Sebastiano Bruno
authors.initials: SB
authors.lastname: Solerte
authors.forename: Ettore
authors.initials: E
authors.lastname: Ferrari
authors.forename: Gianni
authors.initials: G
authors.lastname: Cuzzoni
authors.forename: Eleonora
authors.initials: E
authors.lastname: Locatelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Giustina
authors.forename: Mauro
authors.initials: M
authors.lastname: Zamboni
authors.forename: Nicola
authors.initials: N
authors.lastname: Schifino
authors.forename: Mariangela
authors.initials: M
authors.lastname: Rondanelli
authors.forename: Carmine
authors.initials: C
authors.lastname: Gazzaruso
authors.forename: Marisa
authors.initials: M
authors.lastname: Fioravanti
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000544:Alzheimer Disease / Q000276:immunology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D042501:Angiogenic Proteins / Q000378:metabolism*; D001921:Brain / Q000098:blood supply; D002478:Cells, Cultured; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D015140:Dementia, Vascular / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D008875:Middle Aged; D010446:Peptide Fragments / Q000494:pharmacology; D012016:Reference Values; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D042501:Angiogenic Proteins; D007328:Insulin; D010446:Peptide Fragments; D042461:Vascular Endothelial Growth Factor A; C075222:amyloid beta-protein (1-42); C090308:amyloid beta-protein (40-1); D003687:Dehydroepiandrosterone