Gene, Cell, and Axon Changes in the Familial Amyotrophic Lateral Sclerosis Mouse Sensorimotor Cortex

Abstract

Lower motoneuron abnormalities have been extensively documented in the murine model of familial amyotrophic lateral sclerosis, whereas information on corticospinal neurons in these mice is very limited. We investigated 1) mRNA levels of inflammation-related molecules in the deep layers in which corticospinal neurons reside, 2) corticospinal neurons labeled from tracer injections in the corticospinal tract at the cervical level, 3) axonal damage revealed by A-amyloid precursor protein accumulation, and 4) glial cell activation in the sensorimotor cortex of presymptomatic and endstage superoxide dismutase (SOD)-1 (G93A) mice. We demonstrated induction of inflammatory gene transcripts in the deep layers, early and progressive shrinkage of corticospinal cell bodies and activation of surrounding astrocytes and microglia with upregulation of major histocompatibility complex class I antigen. Accumulation of A-amyloid precursor protein in proximal axonal swellings indicating axonal injury was also evident at the terminal stage in the motor cortex and internal capsule. Glial and axon changes were not observed elsewhere in the cortex. These data reveal that the entire motor circuit is affected in this murine amyotrophic lateral sclerosis model as it is in human amyotrophic lateral sclerosis. Sensorimotor cortical inflammation and progressive corticospinal cell body and fiber damage may reflect transsynaptic signaling of damage from lower motoneurons.

Microglia in ALS: The Good, The Bad, and The Resting

“…Although numerous pathological processes appear to contribute to motoneuron injury in this inexorable disease, neuroinflammation is an underappreciated pathological hallmark in ALS, highlighted by the presence of activated microglia and infiltrating lymphocytes at sites of motoneuron injury (Kassa et al 2009;Henkel et al 2004;Ince et al 1996;Engelhardt et al 1993;Kawamata et al 1992;Troost et al 1990;Lampson et al 1990;Troost et al 1989;McGeer et al 1988). There is considerable morphological and neurochemical evidence for the proliferation and activation of microglia in ALS (Moisse and Strong 2006).…”

On the biomarkers and mechanisms of konzo, a distinct upper motor neuron disease associated with food (cassava) cyanogenic exposure

“…Neuropathology studies (n=3/treatment group) including examination of the cytoarchitecture of the motor cortex and spinal cord (Nissl staining), expression of neuronal choline acetyltransferase (ChAT, immunohistochemistry for lumbar motor neurons), glial fibrillary acidic protein (GFAP) in the aforementioned areas, and ultrastructural studies were conducted using previously described techniques (Kassa et al, 2009; Tshala-Katumbay et al, 2009). Treatment and handling of rats were done in accordance with the institutional (OHSU) guidelines for care and use of laboratory animals.…”

Neuroinflammation in the pathogenesis of Alzheimer’s disease. A rational framework for the search of novel therapeutic approaches

“…It has been possible to associate a number of neurodegenerative disorders of the CNS to neuroinflammatory events, for example, based on the appearance of high levels of several pro-inflammatory cytokines: AD, Parkinson’s disease (Ferrari et al, 2006), Huntington’s disease (Hsiao et al, 2013), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS; Kassa et al, 2009) among others. In all these diseases neuropathological and neuroradiological studies have been performed providing evidence that neuroinflammatory responses could start prior to a loss of neuronal cells.…”