Dysfunction of the neurovascular unit in ischemic stroke and neurodegenerative diseases: An aging effect

doi:10.1016/j.arr.2016.09.006

Ageing Research Reviews

Volume 34, March 2017, Pages 77-87

https://doi.org/10.1016/j.arr.2016.09.006 Get rights and content

Highlights

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The aging process causes structural and functional impairments to the neurovascular unit (NVU).
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Age-related vulnerability of the NVU increases the risk and exacerbates the severity of ischemic stroke.
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NVU impairment is a cause rather than consequence in aging-related neurodegenerative diseases.
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Alterations of diet and lifestyle could slow down the aging process and ameliorate the risk and outcome of neurological disorders.

Abstract

Current understanding on the mechanisms of brain injury and neurodegeneration highlights an appreciation of multicellular interactions within the neurovascular unit (NVU), which include the evolution of blood-brain barrier (BBB) damage, neuronal cell death or degeneration, glial reaction, and immune cell infiltration. Aging is an important factor that influences the integrity of the NVU. The age-related physiological or pathological changes in the cellular components of the NVU have been shown to increase the vulnerability of the NVU to ischemia/reperfusion injury or neurodegeneration, and to result in deteriorated brain damage. This review describes the impacts of aging on each NVU component and discusses the mechanisms by which aging increases NVU sensitivity to stroke and neurodegenerative diseases. Prophylactic or therapeutic perspectives that may delay or diminish aging and thus prevent the incidence of these neurological disorders will also be reviewed.

Introduction

Aging inevitably starts as early as a new life begins. The factors that influence biological aging fall into two categories, the programmed factors and the damage-related factors. The programmed factors of aging refer to the innate functions that decline or change over time, such as shortened telomeres, reduced production of growth hormone, dysregulated reproductive hormones and dampened immune responses. The damage-related factors occur as results of routine damage at the cellular level and slowly build up to cause aging. These factors usually lead to cellular injuries when they outrange the body’s repair capacity. The best examples of damage-related factors include improperly metabolized cell wastes, insufficiently repaired DNA damage and free radicals derived from normal metabolism or environmental toxins. Both the programmed factors and the damage-related factors of aging may impair cell functions and increase the vulnerability of the brain to injuries or other noxious stimuli. Indeed, aging is an important risk factor for a variety of neurological disorders.

The current understanding of the mechanisms of ischemic brain injury includes an appreciation of multicellular interactions within the neurovascular unit (NVU), which may determine the evolution of blood-brain barrier (BBB) damage, neuronal cell death, glial reaction, and immune cell infiltration (Sohrabji et al., 2013). Evidence from recent studies indicates that aging may aggravate the damage and dysfunction of different components of the NVU and thus accelerate the progress of brain injuries. In this article, we will discuss how aging influences the integrity of the NVU and its subsequent impact on the pathology and outcomes of ischemic stroke. Prophylactic or therapeutic perspectives that may delay or diminish the aging effects will also be reviewed.

Section snippets

Basics of the neurovascular unit (NVU)

In normal brain, neurons are connected to each other through dendrites and axons, forming a network for signal transmission and communication. For many decades, neuronal injury was considered to be the main reason for functional deficits after brain injuries or diseases. Accordingly, almost all therapeutic strategies were targeted at rescuing neurons and repairing neuronal damage. This neurocentric view of brain diseases, however, has been revised as it gradually became clear that the normal

Impact of aging on the components of the NVU

Every living organism is subject to the aging process. The normal functions of an organism rely on the energetic metabolism within mitochondria or cytoplasm. The process of energy metabolization induces damage-related factors of aging, such as oxidative stress, which may cause injuries to cells. Some of the injuries are reversible, but some are not. Those irreversible injuries accumulate over time and eventually impair normal cellular functions. Neurons, with their high metabolic rate, turn out

Vulnerability of aged NVU to ischemic stroke

Structural and functional impairments of a variety of NVU components result in the vulnerability of aged NVU to brain injuries, including ischemic stroke. Ischemic stroke is one of the leading causes of death worldwide, especially among the elderly. Aging is not only a main risk factor of ischemic stroke, but also an indicator of poor outcome (Denti et al., 2010). The pathophysiological process of ischemic stroke can be divided into three phases (Fig. 3): (i) the excitotoxic phase, which

NVU impairment is a cause rather than a consequence in aging-related neurodegenerative diseases

Neurodegenerative diseases could be considered as accelerated aging because their pathophysiological mechanisms share commonalities with the normal aging process (Butterfield et al., 2001). Unlike ischemic stroke, which is explicitly a vascular disease, the relationship between neurodegenerative diseases and age-related NVU impairment seems relatively obscure. However, more and more evidence supports the notion that the impairments in both the microvascular and the neuroglial components of the

Prevention perspectives

Population aging is becoming a serious societal issue worldwide. Age-related changes to the NVU have been increasingly accepted as important factors that promote the vulnerability to ischemic injury and neurodegeneration. Despite the monumental progress in the research on aging, it is so far still impossible to reverse the process of aging in the senile NVU. Nevertheless, alternative approaches have been developed to ameliorate the impact of aging on NVU and protect the aged brain against

Conclusion

Aging is an unescapable and ever-progressing process that affects every living organism from birth. It causes molecular damage, organelle dysfunction and cellular injury in the components of the NVU and leads to structural and functional impairments. As a result, the vulnerability of the NVU to ischemic stroke and neurodegeneration increases with aging. Prophylactic or therapeutic strategies that target at the aging process will bring new hope for management of CNS injuries and diseases.

Sources of support

This work was supported by VA merit grants (I01BX002495 and I01RX000420 to Jun Chen), NIH grants (NS095671, NS089534 and NS45048 to Jun Chen); and the U.S. Department of Veterans Affairs Senior Research Career Scientist Award (to Jun Chen).

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Dysfunction of the neurovascular unit in ischemic stroke and neurodegenerative diseases: An aging effect

Highlights

Abstract

Introduction

Section snippets

Basics of the neurovascular unit (NVU)

Impact of aging on the components of the NVU

Vulnerability of aged NVU to ischemic stroke

NVU impairment is a cause rather than a consequence in aging-related neurodegenerative diseases

Prevention perspectives

Conclusion

Sources of support

Brain Behav. Immun.

Neuron

Trends Neurosci.

Am. J. Clin. Nutr.

J. Microbiol. Immunol. Infect.

Neuropharmacology

Brain Res.

Neuroscience

Mol. Ther.

Trends Immunol.

Prog. Neurobiol.

Mech. Ageing Dev.

Exp. Gerontol.

Am. J. Clin. Nutr.

Prog. Neurobiol.

Neurobiol. Aging

Prog. Neurobiol.

Mol. Cells

J. Stroke Cerebrovasc. Dis.

Neuroscience

Prog. Neurobiol.

Immun. Ageing

Cytotherapy

Exp. Neurol.

Prog. Neurobiol.

Kidney Int.

Exp. Neurol.

Prog. Neurobiol.

Neurotherapeutics

Pharmacol. Res.

Parkinson's Dis.: Cell Vulnerability Dis. Progression

Neuroscience

Prog. Neurobiol.

Prog. Neurobiol.

Neurobiol. Aging

Neurobiol. Aging

Prog. Neurobiol.

Prog. Neurobiol.

Astrocyte-endothelial interactions at the blood-brain barrier

Nat. Rev. Neurosci.

The role of activated microglia and resident macrophages in the neurovascular unit during cerebral ischemia: is the jury still out?

Med. Princ. Pract.

Role of Astrocytes in Neurodegenerative Diseases

Commensal microbiota affects ischemic stroke outcome by regulating intestinal gammadelta T cells

Nat. Med.

The role of pericytes in blood-vessel formation and maintenance

Neuro.-Oncol.

Dysfunction of dopamine homeostasis: clues in the hunt for novel Parkinson's disease therapies

FASEB J.

The CNS microvascular pericyte: pericyte-astrocyte crosstalk in the regulation of tissue survival

Fluids Barriers CNS

Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms

Proc. Natl. Acad. Sci. U. S. A.

Endothelial aging

Cardiovasc. Res.

Apoptotic mechanisms after cerebral ischemia

Stroke

Brain oxidative stress in animal models of accelerated aging and the age-related neurodegenerative disorders, Alzheimer's disease and Huntington's disease

Curr. Med. Chem.

Degeneration of an intracellular ion channel in the primate lineage by relaxation of selective constraints

Mol. Biol. Evol.