Chapter 4 - Neurovascular Aspects of Amyotrophic Lateral Sclerosis

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Abstract

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease with a complicated and poorly understood pathogenesis. Strong evidence indicates impairment of all neurovascular unit components including the blood–brain and blood–spinal cord barriers (BBB/BSCB) in both patients and animal models. The present review provides an updated analysis of the microvascular pathology and impaired BBB/BSCB in ALS. Based on experimental and clinical ALS studies, the roles of cellular components, cell interactions, tight junctions, transport systems, cytokines, matrix metalloproteinases, and free radicals in the BBB/BSCB disruption are discussed. The impact of BBB/BSCB damage in ALS pathogenesis is a novel research topic, and this review will reveal some aspects of microvascular pathology involved in the disease and hopefully engender new therapeutic approaches.

Introduction

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with an estimated incidence of 1.6 in 100,000 people per year, and a reported prevalence of 4 per 100,000 (Hirtz et al., 2007). The disorder affects upper and lower motor neurons, leading to progressive muscle atrophy, paralysis, and death typically within 3–5 years from diagnosis (Haverkamp et al., 1995, Rowland and Shneider, 2001). Most ALS cases are sporadic (SALS) with only 5–10% genetically linked (FALS), and of those that have familial etiology, 20% show missense mutations in the Cu/Zn superoxide dismutase (SOD1) gene (Rosen et al., 1993). Numerous hypotheses exist regarding ALS pathogenesis, including glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, neurofilament accumulation, protein mishandling, altered glial function, viral infections, impaired trophic support, and immune imbalance (Bruijn et al., 2004, Consilvio et al., 2004, Deng et al., 2011, Mitchell and Borasio, 2007, Pasinelli and Brown, 2006, Rothstein, 2009, Saleh et al., 2009, Strong et al., 2005, Van Den Bosch et al., 2006), but the roles played by these deficiencies, as primary or cumulative motor neuron insults, still need to be determined.

The blood–brain and blood–spinal cord barriers (BBB/BSCB) have a crucial role in regulating the exchange of molecules between the central nervous system (CNS) and the peripheral blood, and protecting the CNS from hazardous fluctuations in plasma composition (Abbott and Romero, 1996, Ballabh et al., 2004, Bradbury, 1985, Nag, 2003, Pardridge, 1999). Exchange by free diffusion is limited to molecules weighing less than 450 Da; substances with greater size require specific transporting mechanisms (Pardridge, 2005). Endothelial cells and their tight junctions are the main components of the BBB/BSCB system, while astrocyte end-feet, perivascular macrophages, pericytes, and the basement lamina also have integral roles. There is a dynamic interaction between environmental factors and endothelial and CNS resident cells, the basement membrane, and migrated immune cells (Dermietzel and Krause, 1991), continuously modulating the permeability and selectivity of the BBB/BSCB. Therefore, functional or structural impairment of any of the barrier components may impair this system protecting the CNS, thus endangering the cerebral homeostasis.

Impairment of the BBB, BSCB, or blood–cerebrospinal fluid barrier (BCSFB) has been suggested in ALS (Garbuzova-Davis et al., 2007a, Garbuzova-Davis et al., 2007b, Garbuzova-Davis et al., 2008, Garbuzova-Davis et al., 2011, Nicaise et al., 2009a, Nicaise et al., 2009b, Zhong et al., 2008). Although neuronal death seems to be a final event in ALS, and one event associated with most manifestations of the disease, dysfunction or structural damage of the BBB/BSCB or BCSFB may contribute to ALS pathogenesis. Initial reports of altered BCSFB permeability in ALS were published over 25 years ago (Annunziata and Volpi, 1985, Leonardi et al., 1984), and more recent research indicates impairment of the BBB and BSCB, both in animal models and in patients. Indeed, BBB/BSCB leakage is observed in SOD1 animal models of ALS since presymptomatic stage of disease, hence preceding neuronal death (Nicaise et al., 2009a, Zhong et al., 2008). These observations may change the focus of investigation in ALS: from a neuronal-centered to a broader, possibly endothelium-centered approach. Therefore, the classification of ALS as a neurovascular disease (Garbuzova-Davis et al., 2011) provides a basis for future therapeutic studies, investigations perhaps targeting BBB/BSCB repair.

Section snippets

BBB/BSCB Impairment in ALS

The first evidence of BCSFB impairment appeared in the 1980s: abnormal serum proteins and complement in the CSF of ALS patients (Annunziata and Volpi, 1985, Leonardi et al., 1984). These observations were followed by detection of blood-borne substances in the CNS tissue of ALS patients (Donnenfeld et al., 1984), suggesting BBB/BSCB leakage. However, follow-up studies (Bilic et al., 2006, Pirttila et al., 2004) did not confirm the initial findings. A few years later, the topic saw renewed

Future Perspectives

Today, it is known that, beyond being a purely motor neuron disease, ALS involves deleterious influences from an inflammatory and toxic environment, reinforced by the participation of the peripheral immune system, all of which contribute to motor neuron death (Rothstein, 2009). Inflammation is a key element in the process of motor neuron degeneration, involving participation of activated microglia and astrocytes, T lymphocytes, IgG, and numerous cytokines observed in the brainstem and spinal

Conclusion

There is compelling evidence that the neurovascular unit (Hawkins and Davis, 2005, Vangilder et al., 2011) is impaired in both patients and animal models of ALS. Functional leakage of proteins, increased cell migration to the CNS, impairment of tight junction and transporter systems, activation of metalloproteinase, altered basement membrane composition, degeneration of endothelial cell and astrocyte end-feet and, more recently, blood flow alterations contribute to the idea of microvascular

Acknowledgments

This work was supported in part by the Muscular Dystrophy Association (Grant #92452) and the USF Department of Neurosurgery and Brain Repair.

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