P1-300: Age and brain region specific alterations in mRNA levels of Aβ-degrading enzymes; IDE and NEP

Abstract

Accumulation of amyloid β–protein (Aβ) is a fundamental feature of Alzheimer's disease (AD). Factors that influence expression and activity of the Aβ degrading enzymes, insulin degrading enzyme (IDE) and neprilysin (NEP) towards Aβ are potentially relevant to the etiology of AD. To study how the pathological accumulation of Aβ modifies its own degradation, we measured the relative mRNA levels of these proteases in double transgenic APP/PSEN1 (Tg) mice and their non–transgenic littermates. Additionally, to study age and region specific expression, we measured the relative mRNA levels of IDE and NEP as a function of age and brain region in mice and humans. Real–time polymerase chain reaction (PCR) quantification method was used, which is a rapid and sensitive method that requires very small sample sizes. Our data revealed up–regulation of cortical IDE and NEP mRNA levels in AD patients and Tg mice compared to the respective controls. Interestingly, up–regulation of IDE mRNA levels co–occurred with increased Aβ40 and Aβ42 production. In the ventral cortex of Tg mice and non–transgenic littermates, mRNA levels of NEP decreased significantly with aging. This observation is consistent with the idea that the gradual down–regulation of NEP expression, resulting in a corresponding elevation in the steady–state levels of Aβ, over a decade or more, may cause Aβ accumulation that triggers the AD pathological cascade. Additionally, higher mRNA levels of IDE and NEP were detected in the human cerebellum than in the frontal cortex, which may partly explain why cerebellum exhibits only minor plaque pathology. These data suggest that age– and region–specific changes in the proteolytic clearance of Aβ make an important contribution to pathogenic mechanisms in AD.