| Summary: | Alzheimer's disease is the most common form of dementia that presents a growing dilemma worldwide. Alzheimer's disease is neuropathologically characterized by cerebral atrophy accompanied by deposition of senile plaques and neurofibrillary tangles. The plaques are primarily composed of the amyloid beta peptide (AP), which is produced following processing of the amyloid precursor protein (APP) by the proteases beta- and gamma-secretase. A familial link can be found in approximately half of all Alzheimer's disease cases. In a few families the disease is caused by pathogenic mutations located on three different genes encoding presenilin (PS) 1, PS2 and APP. PS is an important component of the complex executing gamma-secretase processing of APP. A detailed characterization of the distribution of PS1 mRNA revealed that PS1 was found both in neurons and peripheral tissues such as testis, kidney, spleen, adrenal gland and thymus. This distribution indicated that the function of PS1 was likely also systemic, and not only found in processes involved with Alzheimer's disease. This idea has been confirmed more recently with the realization that the proteolytic activities of the gamma-secretase complex act on both Notch signaling pathways as well as APP processing. Neuronal cell-death in Alzheimer's disease has been suggested to involve both inflammatory and apoptotic reactions. One way of investigating apoptotic cell death in the hippocampus, a region gravely affected in AD, is by treating rats with the neurotoxic agent trimethyltin (TMT). Using this model, hippocampal neurons may be studied in order to investigate relationships in the neurodegenerative pathway. Following TMT-induced intoxication, a significant reduction of mRNA encoding the APP isoform consisting of 695 amino acids (APP695) was observed. In contrast mRNA encoding APP containing a Kuniz protease inhibitor domain (APP-KPI) as well as PS1 were unaltered despite neuronal loss. This might be explained by mRNA expression in invading astrocytes. One week after ...
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