EFFECTS OF TEMPERATURE ON AMYLOID PRECURSOR PROTEIN (APP) METABOLISM IN CULTURED ASTROCYTES

Abstract

Alzheimer’s disease (AD), the most common type of senile dementia, is characterized by the presence of β-amyloid (Aβ)-containing neuritic plaques and tau-positive neurofibrillary tangles and the loss of neurons in specified regions of the brain. Evidence suggests that increased levels/aggregation of Aβ peptides can contribute to neuronal loss and subsequent development of AD pathology. These Aβ peptides are generated from their precursor, amyloid precursor protein (APP), which is processed proteolytically by either the amyloidogenic β-secretase or the non-amyloidogenic α-secretase pathways. Some recent studies emphasize that ambient temperature may influence disease progression and/or pathology in animal models and AD patients. However, very little is known how the temperature can influence Aβ metabolism in different cell types in the brain. In the present study I used astrocytes, the most abundant glial cells in the brain, to evaluate how temperature can influence APP processing leading to the generation of Aβ-related peptides. My data show that viability of cultured astrocytes was significantly affected in hypothermic (27oC) compared to normal (37oC) and hyperthermic (40oC) conditions. Accompanying these changes, the levels of APP and its cleaved products are increased in the hyperthermic condition, whereas APP- processing enzymes are differentially altered in hypothermic, normal and hyperthermic conditions. The secretory levels of Aβ1-40 are markedly increased but its degrading enzyme neprilysin is found to be decreased in the hyperthermic condition in a time-dependent manner. This study also indicates that markers of the autophagic lysosomal system, a major site of APP metabolism, are also significantly altered following exposure to different temperature conditions. These results, taken together, indicate that ambient temperature may influence AD pathology by regulating APP metabolism in astrocytes.