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.

Temporal and Spatial Changes in the Pattern of Iba1 and CD68 Staining in the Rat Brain Following Severe Traumatic Brain Injury

“…However, microglias are now the subject of numerous recent publications and heated debate [10]. Activation of microglia has been linked to neuropathologies, including chronic pain, amyotrophic lateral sclerosis (ALS) and Alzheimer's disease [6] [11] [12]. Paradoxically, activation of microglia has been linked to both neuroprotection [3] [13] and neurotoxic events [14] [15].…”

Far beyond the motor neuron: the role of glial cells in amyotrophic lateral sclerosis

“…Although classically related to neuronal regulation functions, astrocytes are involved in regulation of the extracellular microenvironment in neurotransmitters at synapses and during their developmental stages; control of signaling of CNS vascular development (including modulation of blood-brain-barrier development); neurotrophic support and stimulation for diverse neurons, maintenance of intercellular signaling (including modulation of excitatory synaptic transmission via release and propagation of glutamatergic stimuli); and neurometabolites and ionic regulation and homeostasis (acid and fluid equilibrium) 3,8,13,17,18,19 . The main mechanism involving astrocytes in ALS pathophysiology is dysfunction of glutamate transporters 20 with loss of the astroglial glutamate transporter EAAT2 (by aberrant RNA splicing, exon skipping and intron retention) in the motor cortex and in the anterior horn of the spinal cord, disclosing its important function in excitotoxic damage in sporadic ALS.…”

“…Microglia result from differentiation of precursors of the monocyte/mesodermal lineage of hematopoietic stem cells that normally protect against microbial infection, abnormal aggregated protein, immunoglobulin-antigen complexes and microhemorrhagic content 3,21 . Microglial activation is a common hallmark of many neurodegenerative diseases, including ALS, despite the fact that it results mainly from proliferation of myeloid precursor cells 22 .…”

“…There is a fine immune cross-talk in ALS pathogenesis in a suggestive immunopattern shown by reactive microglia (with a mixture of minor expression of CX3CL1 and its receptor and CD200 and its receptor and major expression of IL-6, IL-12, TNF-α and reactive oxygen species); activated macrophages (with higher expression levels of IL-1β, COX2 and glycoprotein CD68), reactive astrocytes (raised SDF-1α); and reactive T-lymphocytes (starting with a preponderance of regulatory T lymphocytes, and, during progression, with a predominance of homolog effector T lymphocytes with reduction of their neuroprotector effect with raised reactive oxygen species, inducible nitric oxide synthase and NOX2/phagocyte oxidase gp91phox) 3,13 . Environmental factors and extraneuronal disturbances are also essential in its immunopathogenesis.…”

Amyotrofik lateral skleroz: klinik özellikler ve güncel tedavi yaklaşımları

“…Bu inflamasyonu azaltmak, büyüme faktörlerini artırmak ile mümkün olabilir 25 . Parkinson ve Alzheimer hastalığında olduğu gibi ALS'de de non-nöronal hücrelerin nöronal hücre kaybına katkıda bulunduğu düşünülmektedir 9,20 .…”