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Changes in APP, PS1 and other factors related to Alzheimer’s disease pathophysiology after trimethyltin-induced brain lesion in the rat

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Abstract

Trimethyltin (TMT) chloride induces limbic system neurodegeneration, resulting in behavioral alterations including cognitive deficits. Different factors related to Alzheimer’s disease (AD) were studied after TMT lesion in Sprague-Dawley rats. The expression of amyloid precursor protein (APP) containing 695 amino acids (APP695), APP containing the Kuniz protease inhibitor domain (APP-KPI), presenilin 1 (PS1), c-fos and IL-1β was investigated at different timepoints after a single TMT injection (7 mg/kg i.p.) using in situ hybridization and immunohistochemistry.

After the TMT treatment, extensive degeneration of pyramidal neurons was observed in the CA3 region of the hippocampus, concomitant with neurodegeneration in the outer layer of the CA1 region and layer II of enterhinal and piriform cortex. The affected regions showed abundant condensed eosinophilic and TUNEL-positive neuronal cells, that were apparent at day 4 after TMT, increasing to day 7 and subsequently disappearing. In the affected regions the levels of APP695 mRNA gradually declined with time after the TMT injection. While there was no apparent alteration in the overall expression of APP-KPI or PS1 mRNA, detailed analysis of the CA3c region showed that the mRNA expression shifted from neurons to glial cells. Three days after TMT, neurons in the piriform cortex, the CA3 region and DG expressed high levels of c-fos mRNA that slowly declined to become normalized when analyzed at day 28. At day 7 after TMT a few distinct IL-1β mRNA expressing glial cells were observed in the CA3c region.

Thus, TMT exposure leads to alterations in the expression of APP, APP-KPI, PS1, c-fos and IL-1β in the limbic system. These findings suggest that TMT lesions, not only share certain key features of AD symptomatology and regional neurodegeneration, but also induce effects on important factors related to the pathophysiology of AD.

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  1. Neurotec, Section of Experimental Geriatrics, Karolinska Institutet, Novum KFC, S-141 86, Stockholm, Sweden

    Camilla Nilsberth & Beata Kostyszyn

  2. Bioscience, Local Discovery Research Area CNS and Pain Control, AstraZeneca, S-151 85, Södertälje, Sweden

    Camilla Nilsberth, Beata Kostyszyn & Johan Luthman

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  1. Camilla Nilsberth
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Nilsberth, C., Kostyszyn, B. & Luthman, J. Changes in APP, PS1 and other factors related to Alzheimer’s disease pathophysiology after trimethyltin-induced brain lesion in the rat. neurotox res 4, 625–636 (2002). https://doi.org/10.1080/1029842021000045471

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