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The effect of neurodegenerative diseases on the subventricular zone

Key Points

  • The subventricular zone (SVZ) maintains its ability to produce new neurons and glial cells throughout life.

  • In response to Huntington's disease, the number of proliferating progenitor cells in the SVZ increases approximately threefold and correlates with the advancing pathology in the striatum.

  • In the SVZ in Huntington's disease, the levels of mitogenic compounds such as neuropeptide Y and cannabinoid CB1 receptors are increased, indicating that SVZ cells are preserved despite the nearby pathology.

  • In Parkinson's disease, the nigrostriatal pathway degenerates and, as a result of lowered dopaminergic inputs to the type C cells, there is a reduction in progenitor cell proliferation in the SVZ. Experimentally this can be restored by administering dopaminergic agonists to the SVZ.

  • In the SVZ in Alzheimer's disease, the amyloid plaques appear to be toxic to the progenitor cells and, thus, progenitor cells cannot survive in the SVZ in the presence of this pathology. It is not clear whether the SVZ attempts to increase progenitor cell proliferation, but the net result is decreased SVZ proliferation due to b-amyloid toxicity.

  • The introduction of mitogenic factors to the SVZ progenitors leads to increased proliferation and migration towards sites of injury in the brain. The delivery of a combination of mitogenic factors or transcription factors to the SVZ by viral vectors may lead to improved progenitor cell replacement at the injury site.

Abstract

During brain development, one of the most important structures is the subventricular zone (SVZ), from which most neurons are generated. In adulthood the SVZ maintains a pool of progenitor cells that continuously replace neurons in the olfactory bulb. Neurodegenerative diseases induce a substantial upregulation or downregulation of SVZ progenitor cell proliferation, depending on the type of disorder. Far from being a dormant layer, the SVZ responds to neurodegenerative disease in a way that makes it a potential target for therapeutic intervention.

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Figure 1: Representations of the subventricular zone (SVZ) in the normal brain and of the changes that occur in neurodegenerative disorders.
Figure 2: Representations of possible therapeutic interventions in the subventricular zone (SVZ) for neurodegenerative diseases.

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Acknowledgements

We wish to thank the Swedish Research Council, the Health Research Council of New Zealand and the Neurological Foundation of New Zealand. In particular, M.A.C. is supported as a Wrightson Postdoctoral Fellow. We thank J. Westin for his expertise in making the original illustrations.

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DATABASES

OMIM

Alzheimer's disease

Huntington's disease

Parkinson's disease

Glossary

Ganglionic eminence

An embryonic cluster of nerve cells near the ventricle, where neurons are generated before they migrate to different parts of the brain.

Progenitor cell

A dividing cell that has the capacity to differentiate.

Basal ganglion

A type of specialized nerve cell cluster that is found deep within each cerebral hemisphere and the upper brainstem. Basal ganglia consist of the caudate nucleus, the putamen, the globus pallidus, the sub-thalamic nucleus and the substantia nigra. The basal ganglia assist in initiating movement and in motor control.

Neuroblast

A dividing neuronal precursor cell.

Striatum

The area of the brain that controls movement and balance. It consists of the caudate nucleus and the putamen, and it is connected to and receives signals from the substantia nigra and the cortex.

Rota-rod performance

A motor test that determines the ability of rodents to keep their balance on a rotating cylinder.

Neurosphere culture

A free-floating multidimensional cell structure that is derived from neural stem cells in vitro. Neurosphere assays enable the investigation of the differentiation and proliferative potential of neural stem cells and progenitor cells.

Differentiation

The process whereby an unspecialized cell develops the specialized functions of a mature cell, for example, a neuron, or a liver or muscle cell.

Acute treatment

A remedial action that is administered within the first few hours of a neurodegenerative or necrotic event such as a stroke.

Sub-acute treatment

A remedial action that is administered after the initial neurodegenerative and/or necrotic events of a stroke are over.

Proliferating cell nuclear antigen

(PCNA). A cell-cycle protein that is expressed during, and shortly after, G1 and S-phase. It is used as a marker of recent cell division.

Substantia nigra pars compacta

(SNpc). The area of the brain where dopamine is produced. It is also one of the basal ganglia nuclei.

Levodopa

The most commonly used drug for the treatment of Parkinson's disease. After administration, it is converted into dopamine, such that it raises the levels of dopamine in the brain. Levodopa treatment is an effective control of Parkinson's disease symptoms, however, its long-term use is associated with complications.

Transit-amplifying cell

A type of proliferative stem cell that is able to divide only 3–5 times before all of its daughter cells terminally differentiate.

β-amyloid (Aβ) peptide

A peptide that is derived from amyloid precursor protein. These peptides are the main protein component of amyloid plaques.

Amyloid precursor protein

(APP). A membrane glycoprotein component of fast axonal transport that is cleaved by secretases to give rise to Aβ.

Neural stem cell

A stem cell that is found in adult neural tissue and can give rise to neurons and glial cells.

Radial glial cell

A connective tissue cell that guides the migration of neurons from the SVZ to the cortex. Radial glia are also a major source of cortical neurons during development.

Autologous transplant

A tissue transplant in which a patient's own progenitor cells are removed, expanded in culture and then transplanted back into the disease-affected region.

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Curtis, M., Faull, R. & Eriksson, P. The effect of neurodegenerative diseases on the subventricular zone. Nat Rev Neurosci 8, 712–723 (2007). https://doi.org/10.1038/nrn2216

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