The Study Of Molecular Mechanism Underlying The Neurodegeneration Of PS CDKO Mice And The Rescue Effects By Environmental Enrichment

Alzheimer's disease is an age-related neurodegenerative disease characterized by significant elevation of Aβ level in patients' brain. Presenilins (PS) play an important role in AD pathology, so it is of great importance to identify the function of PS to elucidate the accurate molecular mechanism of AD. PS is a transmembrane aspartic protease. There are two PS genes, PS1 and PS2. Mice lacking both PS1 and PS2 (cDKO) in the forebrain showed AD-like progressive neurodegenerative disease phenotypes, including age-dependent memory decline and forebrain degeneration, which were independent of Aβ level. However, the molecular mechanism of the neurodegenerative phenotype in PS cDKO mice is to be elucidated. The gene expression profiles of the cortex and hippocampus of 3- and 10-month cDKO mice were examined by oligonucletide microarray and Real-time PCR techniques to identify the related genes and signaling pathways.The classical paradigm of the environmental enrichment (EE) involves placing animals in large cages that contain running wheels, colorful tunnels, and assorted toys. It has been well established that EE can enhance the memory of normal and memory-deficient animals, induce brain structural changes and delay onset and progression of several neurodegenerative animal models. In this study, we exposed one-month-old cDKO mice to EE 3 hr daily for 5 months, then tested the effects using behavioral and histological approaches, and analyzed the EE-induced gene expression changes in the cDKO brain using the high-intensity microarray, fluorescence real-time quantitative PCR, immunohistology and western blotting technologies to explore the underlying mechanism of the effects of EE, which might provide some clues for AD therapeutics.1. Gene expression changes in the forebrains of PS cDKO mice at early peroid of neurodegeneration.Fifty-six and forty-six differently expressed genes were identifitied in the cortex and hippocampus of cDKO mice using microarray techniques. Expression changes of...