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 × 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.

Cerebral Angiogenesis and Expression of Angiogenic Factors in Aging Rats after Exercise

“…A recent study demonstrated a decreased release of VEGF in AD (Solerte et al, 2005). However, in other studies, increased VEGF expression was demonstrated in AD and VAD (Pogue and Lukiw 2004;Tarkowski et al, 2002).…”

Vascular Endothelial Growth Factor: Adaptive Changes in the Neuroglialvascular Unit

“…It has been proposed that the increase in VEGF expression levels occurs as a secondary response to hypoperfusion and hypoxia in the AD brain. Nonetheless, a reduction of VEGF has also been described in peripheral immune cells of Alzheimer patients, an observation explained by the toxic effects of -amyloid on VEGF expression [101]. Therefore, the role of VEGF in Alzheimer's is considered hypothetical and further studies are needed.…”

Growth and Trophic Factors, pH and the Na+/H+ Exchanger in Alzheimers Disease, Other Neurodegenerative Diseases and Cancer: New Therapeutic Possibilities and Potential Dangers

“…Recent groundbreaking research reported the recent discovery of a decreased secretion and release of VEGF in the supernatants of circulating natural killer (NK) immune cells in patients with AD compared to normal controls and patients with other types of senile dementias [90]. These findings become even more significant if, as these authors suggest, the importance of VEGF in brain angiogenesis, neuroprotection and cerebrovascular exchange of nutrients is taken into account.…”