Alzheimer?s disease (AD) affects over 4 million people in the US each year. The molecular mechanisms that underlie the pathogenesis of this disease have not yet been elucidated and it is likely that these changes begin well before detectable cognitive impairment occurs. In this study, we examined tissue sliced from the inferior parietal cortex of 4 AD patients by microarray analysis, and compared the data obtained to similar experiments from patients presenting with non-AD related dementia, using pooled, age-matched control patients as a reference. Experiments were run on whole-genome Agilent 44k oligomer arrays, subjected to z-transformation and analyzed by using distance-based gene selection criteria. By performing this type of analysis, we were able to identify changes specific to AD and not simply those that result from the acquisition of changes characteristic to neurodegeneration. AD patients were matched for similar levels of neuritic plaques (P) and neurofibrilatory tangles (T), indicative of their levels of neurodegeneration. Each of the Alzheimer?s, Parkinson?s or other dementia patients was run as an individual sample, and not as pooled RNA. The results from this small pool of AD patients were expanded to a larger set of twelve AD patients using real-time PCR, immunohistochemistry (IHC) and Western blotting. We found that the major groups of differentially expressed genes included genes involved in nervous system development, and neurological disease, and the major signaling pathways affected were heavily biased towards those involved in immune signaling. Gene ontology analysis revealed that the most significant group of differentially expressed genes related to immune related functions include IL-6, IL-8 and IL-28A and to nervous system development and neurological diseases (e.g., aquaporin, FMR1, ECEs). Gene expression between samples was confirmed using real time RT-PCR and Western analysis as well as immunohistological examination of tissue sections. Overall, we believe that both common and distinct biochemical and molecular pathways are involved in both acute and chronic neurodegenerative and neuroinflammatory processes. Understanding the commonality between these various pathways may provide valuable information into the diagnosis and control of these disease states.
