Early Signs of Neuroinflammation in the Postnatal Wobbler Mouse Model of Amyotrophic Lateral Sclerosis.
Maria MeyerAnalia LimaMaria Claudia Gonzalez DeniselleAlejandro Federico De NicolaPublished in: Cellular and molecular neurobiology (2022)
The Wobbler mouse is an accepted model of sporadic amyotrophic lateral sclerosis. The spinal cord of clinically symptomatic animals (3-5 months old) shows vacuolar motoneuron degeneration, inflammation, and gliosis accompanied by motor impairment. However, data are not conclusive concerning pathological changes appearing early after birth. To answer this question, we used postnatal day (PND) 6 genotyped Wobbler pups to determine abnormalities of glia and neurons at this early age period in the spinal cord. We found astrogliosis, microgliosis with morphophenotypic changes pointing to active ameboid microglia, enhanced expression of the proinflammatory markers TLR4, NFkB, TNF, and inducible nitric oxide synthase. The astrocytic enzyme glutamine synthase and the glutamate-aspartate transporter GLAST were also reduced in PND 6 Wobbler pups, suggesting excitotoxicity due to impaired glutamate homeostasis. At the neuronal level, PND 6 Wobblers showed swollen soma, increased choline acetyltransferase immunofluorescence staining, and low expression of the neuronal nuclear antigen NeuN. However, vacuolated motoneurons, a typical signature of older clinically symptomatic Wobbler mice, were absent in the spinal cord of PND 6 Wobblers. The results suggest predominance of neuroinflammation and abnormalities of microglia and astrocytes at this early period of Wobbler life, accompanied by some neuronal changes. Data support the non-cell autonomous hypothesis of the Wobbler disorder, and bring useful information with regard to intervening molecular inflammatory mechanisms at the beginning stage of human motoneuron degenerative diseases.
Keyphrases
- amyotrophic lateral sclerosis
- spinal cord
- neuropathic pain
- spinal cord injury
- inflammatory response
- nitric oxide synthase
- poor prognosis
- mouse model
- cerebral ischemia
- oxidative stress
- preterm infants
- nitric oxide
- lipopolysaccharide induced
- electronic health record
- immune response
- rheumatoid arthritis
- pregnant women
- binding protein
- endothelial cells
- machine learning
- cell therapy
- big data
- cognitive impairment
- late onset
- single cell
- early onset
- adipose tissue
- artificial intelligence
- deep learning
- gestational age
- nuclear factor