Astrocytes in Physiology
The brain is the most complex organ in human. It is a dynamic structure, able to adapt itself to the environmental changes with extreme plasticity occurring as a result of normal physiological processes or during pathological events. For these reasons, the cells that compose it are highly specialized and allow the realization of important functions within the reduced volume of the skull. This implies the existence of a system able to regulate the homeostasis of this system in a highly effective manner. This task is given to the neuroglial cells, which can be considered as the intrinsic brain defense system [1, 2].
The cells of the neuroglia consist of a heterogeneous cell population, which comprises astrocytes, oligodendrocytes, microglia, and NG2-positive cells. Although each of these cell groups has common features, a marked variability has been highlighted in their functions in different brain regions and during brain development .
Despite the profound differences among the cells of the neuroglia, they all work to preserve the structural integrity and functionality of the brain .
Astrocytes represent the most abundant and morphologically heterogeneous neuroglial cells, and they are involved in a remarkable number of active functions of the central nervous system (CNS) . These cells are responsible for a wide variety of complex and essential functions in the brain. For these reasons, astrocytes are often defined as “homeostatic neuroglial cells.”
Astrocytes are involved in the morphological homeostasis participating in the formation of the blood–brain barrier. They participate in the structural organization of the gray matter shaping it through the creation of nonoverlapping microanatomical domains integrated into astroglial syncytia through gap junctions. This organization allows a long-distance communication within glial networks . Astrocytes are also in close contact with blood vessels and smooth muscles of the precapillary arterioles, and by releasing several molecular mediators (such as prostaglandins, nitric oxide, and arachidonic acid), they influence blood vessel diameter and blood flow according to brain local activity [7, 8].
Astroglia are importantly involved in maintaining the ion, pH, and transmitter homeostasis of the synaptic interstitial fluid . These cells are endowed with transporters for the uptake of K+, Na+/H+ exchanger, and bicarbonate transporter [3, 10]. In addition, astrocytes participate in the regulation of water homeostasis as they express the aquaporin-4 (AQP4) water channel . Astrocyte processes at synapses also exert fundamental roles in transmitter homeostasis by expressing high levels of transporters for neurotransmitters (such as glutamate, GABA, and glycine) .
According to the so-called tripartite synapse hypothesis, the synapses in the CNS are constituted by three elements: the perisynaptic astroglial processes, the presynaptic neuron, and the postsynaptic one . In this architecture, astrocytes exert a dual role. These cells in fact can sense the transmitter release as they express many neurotransmitter receptors, and, on the other side, astrocytes can modulate the efficacy of the synapse by releasing gliotransmitters (i.e., glutamate, GABA, ATP, and d-serine), thus exerting an accurate modulation of synaptic transmission .
Astroglial cells defend the CNS from all types of insults and disease through a process called reactive gliosis . The astrogliosis has been viewed for long time as a detrimental response; however, growing evidence has demonstrated its critical role in neuroprotection. This process is switched on in response to lesions of various etiologies that occur in the CNS (i.e., brain trauma, infections, diseases, and genetic predisposition) and is essential for limiting the area of damage and for the postinsult remodeling and recovery of neural function. Therefore, astrocytes change their morphology and (or) physiology. These changes range from reversible alterations to long-lasting scar formation with rearrangement of tissue structure, in a manner proportionally dependent on the primary insult .
This review will investigate the role of astrocytes in specific neurological disease states and highlight potential therapeutic opportunities.
Astrocytes in Pathology
In a novel point of view, astrocytes cannot be just considered as passive supportive cells deputed to preserve neuronal activity and survival. Nowadays, it is recognized that many levels of brain homeostasis are under their control and that astroglial cells could be correctly considered as the brain defense agents. Given their pleiotropic functions, it is not surprising that their dysfunction is an important contributor to neurological disorders.
The response of astroglia in pathological conditions is very heterogeneous. Indeed, in some circumstances, it is possible to observe morphological changes of these cells that become hypertrophic and proliferate, leading to the so-called reactive state, whereas other pathological situations are characterized by astro-degeneration with consequent loss of their physiological supportive functions (Fig. 1).
Alzheimer's disease (AD) is the most common late-onset, progressive, and age-dependent neurodegenerative disorder associated with dementia [16, 17]. It is clinically characterized by the impairment of the cognitive functions and profound neuronal loss, whereas the neuropathological hallmarks include deposit of beta-amyloid (Aβ) fibrils in senile plaques (SP) and accumulation of hyperphosphorylated tau protein filaments in neurofibrillary tangles (NFTs) . Familial AD constitutes only a small proportion (about 2%) of cases, whereas the vast majority are sporadic (late onset) with unknown etiology.
The role of astrocytes in AD pathology is now widely established. In fact, although SP and NFTs are pathogenomic, in vitro and in vivo findings have demonstrated that Aβ fragments promote a marked neuroinflammatory response sustained by astroglial cells, accounting for the synthesis of different cytokines and proinflammatory mediators [19, 20]. The glial involvement in the pathogenesis of AD was suggested by Alois Alzheimer himself, who found that glia populated SP and closely contacted damaged neurons. Astrocytes respond quickly by modifying their morphology and functions. Their reactive state is recognized as a condition with potentially beneficial and destructive consequences .
Neuropathological studies in human brains, demonstrating the activation of glial cells, have been corroborated by studies in which Aβ-exposed and activated astrocytes overproduce proinflammatory signals, which in turn trigger a neurodegenerative cascade [21, 22], setting-up a self-sustained cycle whereby neuronal damage and astrogliosis foster an inflammatory response [13, 19]. Thus, inflammatory process, once initiated, may contribute independently to neural dysfunction and cell death . Investigations with transgenic animal models of AD have strongly supported the assumption that inflammation is a key component of disease pathology and have put forth the hypothesis that besides the sustained production of pathogenic substances, astrocytes, in transition to the inflammatory state, fail to provide their neurosupportive functions, making neurons more vulnerable to toxic molecules . Therefore, because of their crucial role in AD pathology, targeting neuroinflammation might be an effective therapeutic strategy in AD, so that astrocytes may be reasonably regarded as a promising new target for innovative treatments . This notion is corroborated by findings of investigations in experimental models of AD in which newly identified anti-inflammatory molecules selectively suppressed proinflammatory cytokine production in astroglia, resulting in a significant attenuation of neuroinflammation/neurodegeneration processes and consequently in behavioral improvements [26-29].
Parkinson's disease (PD) is a common neurodegenerative disorder whose clinical manifestations include resting tremor, rigidity, slowness of movements, and postural instability. This disease is characterized by the loss of dopaminergic neurons in the ventral midbrain with cell bodies in the substantia nigra pars compacta that project to the striatum, with a lesser effect on dopamine neurons in the ventral tegmental area . Both the cause of the disease and the mechanism of neuronal degeneration in PD remain unknown.
A definitive link has been demonstrated between mutations in specific genes and heritable forms of PD . Although some of these mutations can be found in higher frequency among certain ethnic populations, together they account for only a small percentage (perhaps up to 15%) of all PD cases. For the idiopathic or nonfamilial forms of PD, the prevailing view is that the causes are multifactorial and that genetic predispositions, environmental toxins, and aging are likely to be important factors in disease initiation and progression .
The role of astrocytes in PD is poorly understood, although available data suggest that these cells may have a pathogenic role in PD. Interestingly, the substantia nigra has less astrocytes when compared with other brain regions, and this may explain the specific vulnerability of neurons of this area to stress factors. In addition, in the early stages of PD, astrocyte atrophy and failure to support dopaminergic neurons have been highlighted . This may suggest an important role in the development of PD. On the contrary, the late stages of such disease are characterized by a reactive astrogliosis with the subsequent production and accumulation of proinflammatory and cytotoxic factors , feeding the inflammatory state accompanying neurodegeneration.
Multiple sclerosis (MS) is the most common disabling neurological disease of young adults. At onset, MS can be clinically classified into relapsing remitting MS (85–90% of patients) or primary progressive MS. It is a chronic autoimmune disease characterized by a marked neuroinflammation and neurodegeneration. Neurodegeneration occurs as a consequence of axonal damage, which can be induced directly by the inflammatory attacks and/or by the demyelination process . Growing evidence indicates that the loss of physiological functions of astrocytes may significantly contribute to MS progression . The plaques of demyelination are often surrounded by reactive astrocytes . In addition, it is possible to detect a diffuse reactive astrogliosis both in the white and in the gray matter. These astrocytes exhibit alterations in cytological features and unusual nuclei, showing enlarged body and multiple distinct nuclei . As current therapies are partly effective in the early stages of the disease and display very limited benefits in patients affected by progressive MS, studies concerning the potential involvement of astrocyte function modulators are strongly encouraged.
Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the degeneration of motor neurons located in the cortex, in the brain stem, and in the spinal cord. The ALS exists in two different forms: the familiar form that constitutes ∼10% and the sporadic form. About 20% of ALS cases are associated with dominant mutations in the gene encoding for Cu-Zn superoxide dismutase (SOD1), which is the mutation used to create the animal models of this pathology.
ALS is generally associated with astrogliosis; however, this process follows a marked astroglial degeneration with atrophy that precedes the neuronal death and the clinical manifestations. It has been demonstrated that the astroglial degeneration is a process specific for the astrocytes bearing the SOD1 mutation, which becomes much more vulnerable to glutamate toxicity through mGLU5 receptors . In addition, astrocytes may also exert neurotoxic effects in ALS as they release toxic factors and assist microglial activation and infiltration, thus exacerbating astrogliosis [39, 40].
Epileptic brain tissue is characterized by recurrent spontaneous seizures due to hyperexcitability and hypersynchrony of neurons. Another prominent feature is the alteration of astrocyte functions that may cause seizures or promote epileptogenesis . Reactive astrocytes occur both in animal models of epilepsy and in brain tissue from patients with medically intractable seizure . More specifically, it is possible to observe a profound astrogliotic reaction with astrocytes undergoing morphological and functional changes. These cells display changes in glutamate transporters, as well as reduction in the glutamine synthetase activity , impeding glutamate clearance and thus leading to the extracellular accumulation of such neurotransmitter. Furthermore, reactive astrocytes show reduction in the AQP4 expression that may lead to perturbed water flux and altered K+ buffering, thus increasing propensity for seizures [44, 45].
In addition, astrocytes play a role in epilepsy through the modulation of microvasculature. Indeed, some evidence highlights alterations in the vascular permeability promoting entry of substances in the brain parenchyma, such as circulating leukocytes and serum proteins, facilitating epileptogenesis . Another crucial feature in epilepsy is the destruction of the astrocyte domain organization. It has been reported that neighboring astrocytes in epileptic mice showed a 10-fold increase in overlap of processes concurrent with increased spine density on dendrites of excitatory neurons .
It is a rare, progressive, and nonfamilial leukodystrophy affecting the CNS white matter with frontal lobe preponderance. Clinically, Alexander disease is characterized by macrocephaly, abnormal white matter, epilepsy, and developmental delay and is most commonly diagnosed in its infantile form, with onset before 2 years of age. The most distinctive pathological feature is widespread deposition of cytoplasmic inclusion, termed “Rosenthal fibers,” throughout CNS, mainly in perivascular, subpial, and subependimal astrocytes . Among the known components of Rosenthal fibers are the intermediate filament protein glial fibrillary acid protein (GFAP), small heat-shock protein, and plectin, a filament-binding protein . This illness represents the clearest example of astrocytes acting as the primary culprit in the disease. The genetic basis is the presence of dominant gain-of-function mutations in the GFAP gene , which is expressed almost exclusively in astrocytes. The fact that GFAP is not expressed in neurons or oligodendrocytes implies that the cellular degeneration in the Alexander disease is secondary to disrupted or pathological interactions between astrocytes and other cell populations.