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Neurovascular signalling defects in neurodegeneration

Nature Reviews Neuroscience volume 9, pages 169–181 (2008)Cite this article

Key Points

  • The vascular and nervous systems share a variety of mechanisms and developmental cues, and this results in their growth along common anatomical pathways. It is therefore not surprising that they continue to share similar survival signals throuough adult life and, possibly, in disease.

  • Vascular defects are a common feature of several neurodegenerative disorders, for example, Alzheimer's disease, Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), and they often arise before the onset of neuron loss and neurological symptoms.

  • Several molecules that provide pro-survival signals to both the nervous and vascular systems have been identified. Some of these molecules, which are referred to as angioneurins, were originally discovered as neurotrophic factors, whereas others were discovered as angiogenic factors.

  • VEGF is perhaps the best example of an angioneurin. It was initially identified as an angiogenic factor, but it in fact emerged in the evolution of animals that lack a vascular network, in which it regulates neural developments. Emerging new evidence points to an important role for VEGF in neurodegeneration, both in animal models and in human diseases.

  • Angioneurins might affect the onset and progression of neurodegeneration by pleiotropic mechanisms: they directly protect neurons from ischaemia, toxins and other causes of injury; promote neurogenesis; modulate synaptic plasticity; stimulate neurite extension and branching; and promote myelination.

  • The translation of these concepts to therapy is leading to the development of novel strategies to treat animal models of motor-neuron diseases, such as ALS, PD, multiple sclerosis and peripheral neuropathies. When and to what extent these findings will provide clinical benefits to patients remains to be seen.

Abstract

It is anticipated that by 2040 neurodegeneration will affect 40 million people worldwide, more than twice as many as today. The traditional neurocentric view holds that neurodegeneration is caused primarily by intrinsic neuronal defects. However, recent evidence indicates that the millions of blood vessels that criss-cross the nervous system might not be the silent bystanders they were originally considered. Indeed, recent genetic studies reveal that insufficient production of angiogenic signals, which stimulate the growth of blood vessels, can cause neurodegeneration. Remarkably, some angiogenic factors can also regulate neuroregeneration, and have direct neuroprotective and other effects on various neural cell types. Here we provide an overview of the molecules that affect both neural and vascular cell processes — to underline their duality, we term them angioneurins. Unravelling the molecular mechanisms by which these angioneurins act might create opportunities for developing new neurovascular medicine.

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Figure 1: Evolution of vascular endothelial growth factor (VEGF) as a multi-tasking neuronal factor.
Figure 2: Principal angioneurins and their receptors.
Figure 3: Effect of angioneurins on the CNS vasculature and neurogenesis.
Figure 4: Effect of angioneurins on neuroprotection and synaptic plasticity.
Figure 5: Angioneurins promote innervation and axon sprouting.

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Acknowledgements

D.L. is supported by the Research Foundation Flanders (FWO), Belgium; S.Z. was supported by the European Union Seventh framework program via a Marie Curie intra European fellowship; P.C. is supported by the ALS Association (ALSA), the Muscular Dystrophy Association (MDA) and the Motor Neurone Disease (MND) Association. The authors also wish to acknowledge all previous and current collaborators, who have contributed to the studies of the neurovascular link.

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Authors and Affiliations

  1. The Center for Transgene Technology and Gene Therapy, Katholieke Universiteit Leuven, Leuven, B-3000, Belgium

    Serena Zacchigna, Diether Lambrechts & Peter Carmeliet

  2. Department of Transgene Technology and Gene Therapy, VIB, Leuven, B3000, Belgium

    Serena Zacchigna, Diether Lambrechts & Peter Carmeliet

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  1. Serena Zacchigna
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Correspondence to Peter Carmeliet.

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Competing interests

P.C. is named as an inventor on a patent application regarding the use of vascular endothelial growth factor to treat amyotrophic lateral sclerosis. The Flanders Interuniversity Institute for Biotechnology (VIB) is one of the joint owners of this patent application, and the said patent application has been licensed to an outside company. Neither VIB nor any of the authors have equity stakes in the company. However, VIB and some of the authors stand to eventually receive royalties.

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frontotemporal dementia

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Glossary

Blood–brain barrier

A structure that protects the brain from toxins in the blood while still allowing essential metabolites to cross. It is composed of tightly packed endothelial cells surrounded by astrocyte cell projections that are termed astrocytic feet.

Ischaemic penumbra

A term that is generally used to define ischaemic but still viable cerebral tissue that surrounds a core non-viable ischaemic zone.

Pleiotropism

The ability of a single protein to have several seemingly unrelated biological actions.

Basement membrane

A structure composed of an electron-dense membrane (the lamina densa) and an underlying network of reticular collagen fibrils that anchors blood vessels and epithelial cells to the loose connective tissue underneath.

Excitotoxicity

Cellular toxicity that involves the activation of glutamate receptors in the CNS. Glutamate, an excitatory amino-acid neurotransmitter, activates different types of ionotropic (ion channel-forming) and metabotropic (G-protein-coupled) receptors. Excessive activation of these receptors by high concentrations of glutamate or by neurotoxins leads to cell death.

Long-term potentiation

(LTP). The increase in synaptic strength that occurs following high-frequency stimulation of a synapse. LTP is thought to be the physiological mechanism that underlies learning and memory in the hippocampus.

Satellite cells

Cells that proliferate and differentiate to form regenerating myotubes in the regenerating muscle.

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Zacchigna, S., Lambrechts, D. & Carmeliet, P. Neurovascular signalling defects in neurodegeneration. Nat Rev Neurosci 9, 169–181 (2008). https://doi.org/10.1038/nrn2336

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