Progression of morphological changes within CNS in a transgenic rat model of familial amyotrophic lateral sclerosis.
An analysis of the dynamics of histological and immunocytochemical changes in the CNS of a transgenic rat model of fALS in various periods of life was performed. Material was obtained from animals on the 60th day of age (4), 93rd day of age (3) and 120th presymptomatic day and from 3 animals in paretic stage of the disease. Formalin-fixed and paraffin-embedded slices were stained with HE and Klüver-Barrera method. Immunoreactions to GFAP, S-100, ferritin, neurofilament, ubiquitin, synaptophysin and tau protein were also performed. Within the brain tissues patchy neuronal loss and dark or ischaemic neurons were dispersed in cortical layers, CA1, CA3 and CA4 hippocampal areas and structures of the hemispheres and brain stem. In the spinal cord, numerous alpha motoneurons were dark or ischaemic. Vacuoles or small pale spots were visible in their cytoplasm. Microspongiosis surrounded some motoneurons, particularly cells subjected to neuronophagy. Neuronophagy, sporadically observed at the age of 60th day, was more extensive on the 93rd day of age, and at the age of 120 days already involved all interneurons of the anterior and posterior horns. In the immune reaction to neurofilament numerous fibres, often thick, fragmented or rosary-like, were observed. They were located within subcortical white matter, external and internal capsules, anterior horns of the spinal cord. Changes became more intensive with age. Astrocytic reactivity was weak in animals on the 60th and 93rd day of life. Non-numerous cells were immunoreactive to GFAP and S-100, although an increase of astrocytic nuclei was observed. On the 120th day of age and in symptomatic stage astrocytic hypertrophy and proliferation were intensive. But from the 60th day of age ubiquitin and tau protein immunopositive material was accumulated in the perinuclear area of astroglial cytoplasm. Immunoreaction of nerve cells to these proteins was negative.


CONCLUSIONS
1) In the subclinical stage of the disease the pathological process within the CNS takes place already on the 60th day of age and its intensity increases with age. 2) Morphological changes are not limited to motor neuronal cells. Various structures of the CNS are damaged. 3) Weak astroglial reaction probably depends on pathological accumulation of ubiquitin and tau protein in cytoplasm. 4) Astroglial cells are probably also a "target" for pathogenic factors in the rat model of fALS.
Rafałowska
Janina
J
Department of Experimental and Clinical Neuropathology, Polish Academy of Sciences Medical Research Centre, 5 Pawińskiego St, 02-106 Warsaw, Poland.
Fidziańska
Anna
A
Dziewulska
Dorota
D
Gadamski
Roman
R
Ogonowska
Wanda
W
Grieb
Paweł
P
D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology*; D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009046:Motor Neurons / Q000473:pathology*; D009410:Nerve Degeneration / Q000473:pathology; D051381:Rats; D013116:Spinal Cord / Q000473:pathology*