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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 × 10⁶ 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-β (Aβ) fragment 1–42, the inactive sequence Aβ_40–1 and Aβ_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 Aβ_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 Aβ_1–42 + insulin promptly abolished the negative effects of Aβ_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.

Background: The study of the natural killer (NK) immune compartment could provide important findings to help in the understanding of some of the pathogenetic mechanisms related to autoimmune thyroid diseases (Graves' disease (GD) and Hashimoto's thyroiditis (HT)). Within this context, it was suggested that alterations in NK cell cytotoxicity (NKCC) and NK production of cytokines might occur in subjects with GD and HT, whereas the normalization of NK functions could potentially contribute to the prevention of the onset or the progression of both diseases. Objective: Due to the hypothesis of alterations in NK in autoimmune thyroid diseases, we were interested to evaluate NKCC in GD and HT patients and to modulate NK function and secretory activity with cytokines and dehydroepiandrosterone sulfate (DHEAS) in an attempt to normalize NK cell defect. Design: We studied 13 patients with recent onset Graves' disease, 11 patients with Hashimoto's thyroiditis at first diagnosis and 15 age-matched healthy subjects. Methods: NK cells were concentrated at a density of 7.75 £ 10 6 cells/ml by negative immunomagnetic cell separation and validated by FACScan as CD16 þ /CD56 þ cells. NK cells were incubated with interleukin-2 (IL-2) and interferon-b (IFN-b) and co-incubated with DHEAS at different molar concentrations for measuring NKCC and the secretory pattern of tumor necrosis factor-a (TNF-a) from NK cells. Results: Lower spontaneous, IL-2-and IFN-b-modulated NKCC was demonstrated in GD and HT patients compared with healthy subjects (P , 0.001). A decrease in spontaneous and IL-2-modulated TNF-a release from NK cells was also found in both groups of patients (P , 0.001). The co-incubation of NK cells with IL-2/IFN-b þ DHEAS at different molar concentrations (from 10 28 to 10 25 M/ml/NK cells) promptly normalized NKCC and TNF-a secretion in GD and HT patients. Conclusions: A functional defect of a subpopulation of NK immune cells, involving both NKCC and the secretory activity, was demonstrated in newly-diagnosed GD and HT patients. This defect can be reversed by a dose-dependent treatment with DHEAS. The impairment of NK cell activity in autoimmune thyroid diseases could potentially determine a critical expansion of T/B-cell immune compartments leading to the generation of autoantibodies and to the pathogenesis of thyroid autoimmunity.

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