Figure 3 VEGF in neurodegenerative disease Figure 3 | VEGF in neurodegenerative disease. a | Amyotrophic lateral sclerosis (ALS). Low vascular endothelial growth factor (VEGF) levels are a risk factor for ALS in humans, and cause ALS-like disease in mice. Low VEGF levels impair spinal cord perfusion and cause chronic ischaemia of motor neurons, and also deprive these cells of vital VEGF-dependent survival and neuroprotective signals. Both mechanisms may contribute to the adult-onset progressive degeneration of motor neurons, with associated muscle weakness and paralysis and, ultimately, death. Other neural cell types, including microglia, astrocytes, oligodendrocytes and Schwann cells, are impaired in ALS, probably contributing to the motor neuron degeneration. Permission obtained from American Society for Clinical Investigation © Storkebaum, E. & Carmeliet, P. J. Clin. Invest. 113, 14–18 (2004). b Alzheimer disease (AD). Recent literature suggests multifactorial pathogenesis resulting from BBB dysfunction and chronic cerebral hypoperfusion, in combination with deleterious effects due to toxic amyloid-β (Aβ) accumulation in the brain parenchyma and blood vessel walls (cerebral amyloid angiopathy). Hypoxia enhances VEGF expression, possibly leading to a hypervascularization response to relieve hypoperfusion. Aβ is reported to inhibit VEGF receptor signalling, although some studies also indicate that Aβ promotes hypervascularization. We do not yet understand the relative importance of these opposing effects of Aβ, or whether hypervascularization co-contributes to disease progression. c | Parkinson disease (PD). The healthy brain (left) shows an intact BBB, functional dopaminergic neurons and normal astrocytes and resting microglia. Compromised blood–brain barrier (BBB) integrity contributes to the pathogenesis of PD by promoting reactive gliosis, resulting in release of VEGF and proinflammatory cytokines by activated astrocytes and microglia. These events further aggravate BBB disruption and promote dopaminergic neuron dysfunction and death. Permission obtained from American Society for Clinical Investigation © Storkebaum, E. & Carmeliet, P. J. Clin. Invest. 113, 14–18 (2004). Lange, C. et al. (2016) Vascular endothelial growth factor: a neurovascular target in neurological diseases Nat. Rev. Neurol. doi:10.1038/nrneurol.2016.88