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Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders

Key Points

  • The neurovascular unit comprises vascular cells (endothelial cells, pericytes and vascular smooth muscle cells (VSMCs)), glial cells (astrocytes, microglia and oliogodendroglia) and neurons.

  • Neurodegenerative disorders such as Alzheimer's disease and amyotrophic lateral sclerosis (ALS) are associated with microvascular dysfunction and/or degeneration in the brain, neurovascular disintegration, defective blood–brain barrier (BBB) function and/or vascular factors.

  • The interactions between endothelial cells and pericytes are crucial for the formation and maintenance of the BBB. Indeed, pericyte deficiency leads to BBB breakdown and extravasation of multiple vasculotoxic and neurotoxic circulating macromolecules, which can contribute to neuronal dysfunction, cognitive decline and neurodegenerative changes.

  • Alterations in cerebrovascular metabolic functions can also lead to the secretion of multiple neurotoxic and inflammatory factors.

  • BBB dysfunction and/or breakdown and cerebral blood flow (CBF) reductions and/or dysregulation may occur in sporadic Alzheimer's disease and experimental models of this disease before cognitive decline, amyloid-β deposition and brain atrophy. In patients with ALS and in some experimental models of ALS, CBF dysregulation, blood–spinal cord barrier breakdown and spinal cord hypoperfusion have been reported prior to motor neuron cell death.

  • Several studies in animal models of Alzheimer's disease and, more recently, in patients with this disorder have shown diminished amyloid-β clearance from brain tissue. The recognition of amyloid-β clearance pathways opens exciting new therapeutic opportunities for this disease.

  • 'Multiple-target, multiple-action' agents will stand a better chance of controlling the complex disease mechanisms that mediate neurodegeneration in disorders such as Alzheimer's disease than will agents that have only one target. According to the vasculo-neuronal-inflammatory triad model of neurodegenerative disorders, in addition to neurons, brain endothelium, VSMCs, pericytes, astrocytes and activated microglia all represent important therapeutic targets.

Abstract

The neurovascular unit (NVU) comprises brain endothelial cells, pericytes or vascular smooth muscle cells, glia and neurons. The NVU controls blood–brain barrier (BBB) permeability and cerebral blood flow, and maintains the chemical composition of the neuronal 'milieu', which is required for proper functioning of neuronal circuits. Recent evidence indicates that BBB dysfunction is associated with the accumulation of several vasculotoxic and neurotoxic molecules within brain parenchyma, a reduction in cerebral blood flow, and hypoxia. Together, these vascular-derived insults might initiate and/or contribute to neuronal degeneration. This article examines mechanisms of BBB dysfunction in neurodegenerative disorders, notably Alzheimer's disease, and highlights therapeutic opportunities relating to these neurovascular deficits.

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Figure 1: Cerebral microcirculation and the neurovascular unit.
Figure 2: Blood–brain barrier transport mechanisms.
Figure 3: Vascular-mediated neuronal damage and neurodegeneration.
Figure 4: The role of blood–brain barrier transport in brain homeostasis of amyloid-β.
Figure 5: A model of vascular damage in Alzheimer's disease.

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Acknowledgements

The author wishes to thank the US National Institutes of Health (grants R37 AG023084, R37 NS34467 and HL63290), the ALS Association (grant 1859) and the Zilkha family for research support. The author also wishes to thank A. Sagare for preparing the illustrations and for valuable help with the reference list.

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Berislav V. Zlokovic is the scientific founder of Socratech LLC, a start-up biotechnology company with a mission to develop new therapeutic approaches for stroke and Alzheimer's disease.

Glossary

Blood–brain barrier

(BBB). A continuous endothelial cell membrane within the neurovascular unit that regulates the entry of cells and molecules into the brain, and maintains the removal of potentially neurotoxic molecules from the brain to blood.

Cerebral β-amyloidosis

This is a key pathological feature of Alzheimer's disease and is caused by accumulation and aggregation of amyloid-β in brain parenchyma.

Cerebral amyloid angiopathy

A vessel disease that is caused by the deposition of amyloid in the vessel wall of small cerebral arteries and capillaries, and that results in cerebral blood flow dysregulation, blood–brain barrier disruption and microhaemorrhages.

Amyloid-β

A small, 4-kDa peptide that accumulates in the brains of individuals with Alzheimer's disease. It forms neurotoxic oligomers and amyloid aggregates that are deposited in the brain parenchyma and around small cerebral blood vessels.

Neurovascular unit

A complex multicellular functional unit of the CNS comprising vascular cells, glial cells and neurons that, together, ultimately determine CNS activities and responses in health and disease.

Pericytes

Mural vascular cells that share a common basement membrane with brain capillary endothelial cells at one end, and that are in direct contact with astrocytes at the other.

Protein C

An endogenous protease that in its active form — activated protein C (APC) — is a prototype of a new, neurovascular medicine that exerts multiple beneficial effects by acting on different types of non-neuronal cells within the neurovascular unit.

Low-density lipoprotein receptor-related protein 1

(LRP1). A cargo endocytic receptor mediating cellular internalization of multiple ligands as well as cell signalling in various cell types of the neurovascular unit.

Neurovascular coupling

This involves a functional change in cerebral blood flow that occurs in accordance, both temporally and spatially, with a change in neuronal activity.

Oligaemia

This is a moderate deficit in the resting cerebral blood flow that, if it persists, often leads to the chronic hypoperfusion and hypoxia in the CNS that is frequently found in the major neurodegenerative disorders before neurodegeneration.

Pinocytosis

This is the nonspecific transport of fluid-filled vesicles across the endothelial cells in capillaries of peripheral organs.

Neurovascular uncoupling

A term defining a diminished cerebral blood flow response to brain activation.

Trojan horses

In relation to the blood–brain barrier, this term is frequently used to describe the facilitated delivery into the brain of an otherwise non-transportable neuroactive therapeutic protein through the formation of a complex with another protein.

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Zlokovic, B. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci 12, 723–738 (2011). https://doi.org/10.1038/nrn3114

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