神经退行性病
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Figure 1｜Changes in the intercellular communications between neurons and non-neuronal cells in case of neurodegenerative diseases.
One of the main factors in the progression of neurodegenerative diseases is neuroinflammation. Microglia, the key players of the immune system in the CNS, take the role of sensing danger signals through their ramified branches. Once they are activated, microglia transform into amoeboid shape and play a dual role in secreting molecules, ranging from anti-inflammatory to proinflammatory functions. In some neurodegenerative diseases, the balance between beneficial and harmful elements of microglia is disturbed. In general, microglia prefer to produce and release neuroprotective agents at disease onset. However, during disease progression, a shift from neuroprotection to neurodegeneration is observed, and microglia start to release harmful molecules such as cytokines and chemokines (Figure 1A). These molecules, having both paracrine and autocrine functions, amplify the inflammatory response and ultimately exacerbate the neurological disease by causing neural cell death. Being a double-edged sword for neurons, microglia can have different effects in various animal models for amyotrophic lateral sclerosis (ALS), the most common motor neuron disease (Cihankaya et al., 2021). Besides the release of cytokines and neurotrophic factors, neurons can communicate with glial cells through direct cell-to-cell interactions. For example, C-X3-C motif chemokine ligand 1 (CX3CL1) is constitutively produced by neurons in the CNS, and surprisingly has only one receptor expressed by microglia, named CX3CR1. CX3CL1 has two different forms:
(i) the membrane-bound form, which acts as a cell adhesion molecule for inflammatory cells and (ii) the soluble form, which is cleaved from the membrane of neurons, and can bind to the CX3CR1 on the microglia (Chapman et al., 2000). Activation of CX3CL1/CX3CR1 signaling by both membrane-bound and soluble CX3CL1 in the case of a neurodegenerative disease controls microglial activation, and consequently the neuron-microglial communication (Mecca et al., 2018). Additionally, internalization of secreted exosomes containing mRNAs, microRNAs, and proteins by neighboring cells in the CNS is another way of intercellular interaction between CNS cells, as all cell types are able to secrete exosomes in the CNS (Meyer and Kaspar, 2017). Based on the content of the exosomes, it is possible to modify gene expression in the target cell and thus affect neuron-glia communication. In conclusion, targeting microglia and shifting the balance towards neuroprotection may be important to delay disease progression and open the way to finding new therapies for neurodegenerative disorders. Astrocytes, the most abundant glial cell type, perform several roles in the CNS, such as providing structural and metabolic support to neurons, maintaining nutrient and ion balance, regulating cerebral blood flow, and modulating transmitter uptake and release. The two most important glutamate transporters in humans, the excitatory amino acid transporter 1 and 2, are mainly localized on the membranes of astrocytes and play a role in glutamate uptake by transporting excess amount of extracellular glutamate (Figure 1B). In neurodegenerative diseases, these glutamate transporters have been shown to be downregulated, resulting in increased levels of synaptic glutamate and thus excitotoxicity in the brain parts associated with the respective diseases (Maragakis and Rothstein, 2006). Besides neurons, astrocytes are able to release glutamate by two different mechanisms: (i) via exocytosis and (ii) via hemichannels, which are activated upon low extracellular calcium levels. Once glutamate is released, its propagation through the astrocyte syncytium can proceed in two pathways. First, released glutamate by neurons can trigger metabotropic glutamate receptors on the astrocyte membrane, which in turn can activate inositol triphosphate (IP3), causing release of calcium from intracellular stores within the astrocytes. This calcium can be transferred to neighboring astrocytes via gap junctions, resulting in formation of calcium waves. Second, increased amount of IP3 may induce adenosine triphosphate release through gap junctions acting in a paracrine manner, which in turn may activate purine receptors on the neighboring astrocytes. This event leads to activation of even more IP3, and consequently triggers more adenosine triphosphate and calcium release through a positive feedback loop. In neurodegenerative diseases, this enormously involved cell-to-cell communication between astrocytes and neurons has been shown to be severely impaired. For example, increased calcium wave signaling among astrocytes during the Alzheimer’s disease (AD) progression and impairment of astrocyte syncytium due to uncoupling of cell-to-cell interactions in Huntington’s disease point to the importance of glial cells in the unhealthy state (Maragakis and Rothstein, 2006). In addition to their role in the glutamate metabolism, astrocytes, which in fact are not part of the immune system, may participate in the neuro-immunological response when neural damage is involved. This process is called reactive astrogliosis and is accompanied with upregulation of the intermediate filament, glial fibrillary acidic protein (GFAP). Colocalization of GFAP+ astrocytes with amyloid-β42 in AD, mutant superoxide dismutase 1 in ALS, and mutant huntingtin in Huntington’s disease has been demonstrated in different studies (Lian and Zheng, 2016). Astrocytes displaying these mutant protein aggregations, together with axonal degeneration, make neurons more susceptible to cell death in the above-mentioned diseases. Studies regarding nitric oxide (NO) have shown its role in both physiological as well as pathological processes and that it can be released by neuronal and glial cells (Contestabile et al., 2012). NO is an important cellular signaling molecule regulating neuronal function. Under physiological conditions, NO is synthesized by neuronal cells following increases in Ca2+-concentration, thus controlling neuronal plasticity and neuronal mechanisms at the pre-synapse. Contrary to initial assumptions that astrocytes synthesize NO only after induced stress, the release of NO from astrocytes also has a modulatory function on neuronal activity under physiological condition (Buskila et al., 2007). However, pathologically elevated glial-derived NO levels are neurotoxic.
Thus, a balance of NO levels as well as a defined interaction between neuron and glia is important for physiological regulation of many neuronal functions. Overall, the dynamic interplay between abnormal astrocytes and neurons can affect healthy astrocytes present in close proximity and worsen a disease state.
Oligodendrocytes insulate the axons of neurons while providing metabolic and physical support. The proliferation and differentiation of oligodendrocytes, as well as myelination of neurons, are directed by oligodendrocyte-neuron signaling, and any dysfunction in this process results in motor, sensory and cognitive deficits, as seen in developmental disorders along with neurodegenerative diseases such as AD, ALS, multiple sclerosis and multiple system atrophy (Ettle et al., 2016; Tognatta and Miller, 2016). Downregulation of myelin-specific proteins in most of neurodegenerative diseases, morphological alterations of the myelin structure in ALS, accumulation of alpha-synuclein proteins in oligodendrocytes of multiple system atrophy patients, metabolic uncoupling of iron and lactate mechanisms in AD and ALS, are some of the events that eventually lead to axonal loss and neurodegeneration during disease progressions (Figure 1C; Tognatta and Miller, 2016).
In contrast to the prevailing idea of limiting neurodegenerative diseases to the CNS, the involvement of peripheral immune system in the progression of these diseases should be considered. Disruption of the blood brain barrier and blood spinal cord barrier in neurodegenerative diseases allows peripheral immune cells to infiltrate the CNS parenchyma, resulting in intimate contact of these cells with neurons (Figure 1D).