Cellular therapy to target neuroinflammation in amyotrophic lateral sclerosis

Abstract

Neurodegenerative disorders are characterized by the selective vulnerability and progressive loss of discrete neuronal populations. Non-neuronal cells appear to significantly contribute to neuronal loss in diseases such as amyotrophic lateral sclerosis (ALS), Parkinson, and Alzheimer's disease. In ALS, there is deterioration of motor neurons in the cortex, brainstem, and spinal cord, which control voluntary muscle groups. This results in muscle wasting, paralysis, and death. Neuroinflammation, characterized by the appearance of reactive astrocytes and microglia as well as macrophage and T-lymphocyte infiltration, appears to be highly involved in the disease pathogenesis, highlighting the involvement of non-neuronal cells in neurodegeneration. There appears to be cross-talk between motor neurons, astrocytes, and immune cells, including microglia and T-lymphocytes, which are subsequently activated. Currently, effective therapies for ALS are lacking; however, the non-cell autonomous nature of ALS may indicate potential therapeutic targets. Here, we review the mechanisms of action of astrocytes, microglia, and T-lymphocytes in the nervous system in health and during the pathogenesis of ALS. We also evaluate the therapeutic potential of these cellular populations, after transplantation into ALS patients and animal models of the disease, in modulating the environment surrounding motor neurons from pro-inflammatory to neuroprotective. We also thoroughly discuss the recent advances made in the field and caveats that need to be overcome for clinical translation of cell therapies aimed at modulating non-cell autonomous events to preserve remaining motor neurons in patients.

Fig. 1

Cross-talk between motor neurons, astrocytes, and immune cells (including microglia, T lymphocytes, and macrophages) in a healthy individual (a) and an ALS patient (b)

Fig. 2

Tripartite synapse in health and in ALS: CNS functions depend on a network that includes both pre- and post-synaptic terminals of neurons and astrocytes. Left In a healthy individual, astrocytes take up glutamate, which is released into the synaptic cleft, through sodium-dependent excitatory amino acid transporter-1 (EAAT1) and -2 (EAAT2; GLT1 in mice). Middle In ALS patients and rodent fALS models, EAAT2 expression is reduced in astrocytes in the motor cortex and spinal cord, which could cause an accumulation of excitotoxic levels of extracellular glutamate and subsequently increase the neuronal intracellular calcium concentration and initiate cascades that regulate motor neuron death. Right Transplantation of healthy astrocytes expressing EEATs into an ALS host could sequester excess glutamate from the synapse and decrease excitotoxicity

Fig. 3

Transplantations of wild-type or genetically engineered astrocytes, microglia, and T-lymphocytes are feasible and potential future therapeutic approaches for ALS