Neuronal gene expression in non-demented individuals with intermediate Alzheimer's Disease neuropathology

Abstract

While the clinical and neuropathological characterization of Alzheimer's Disease (AD) is well defined, our understanding of the progression of pathologic mechanisms in AD remains unclear. Post-mortem brains from individuals who did not fulfill clinical criteria for AD may still demonstrate measurable levels of AD pathologies to suggest that they may have presented with clinical symptoms had they lived longer or are able to stave off disease progression. Comparison between such individuals and those clinically diagnosed and pathologically confirmed to have AD will be key in delineating AD pathogenesis and neuroprotection. In this study, we expression profiled laser capture microdissected non-tangle bearing neurons in 6 post-mortem brain regions that are differentially affected in the AD brain from 10 non-demented individuals demonstrating intermediate AD neuropathologies (NDAD; Braak stage of II through IV and CERAD rating of moderate to frequent) and evaluated this data against that from individuals who have been diagnosed with late onset AD as well as healthy elderly controls. We identified common statistically significant expression changes in both NDAD and AD brains that may establish a degenerative link between the two cohorts, in addition to NDAD specific transcriptomic changes. These findings pinpoint novel targets for developing earlier diagnostics and preventative therapies for AD prior to diagnosis of probable AD. We also provide this high-quality, low post-mortem interval (PMI), cell-specific, and region-specific NDAD/AD reference data set to the community as a public resource.

Fig. 1

Common expression changes in NDAD and AD. Regional dendrograms of statistically significant genes (P< 0.01, corrected for multiple testing) demonstrating parallel expression changes are shown. Genes shown have the greatest changes in expression for both the NDAD vs. controls analysis and AD vs. controls analysis.

Fig. 1

Common expression changes in NDAD and AD. Regional dendrograms of statistically significant genes (P< 0.01, corrected for multiple testing) demonstrating parallel expression changes are shown. Genes shown have the greatest changes in expression for both the NDAD vs. controls analysis and AD vs. controls analysis.

Fig. 1

Common expression changes in NDAD and AD. Regional dendrograms of statistically significant genes (P< 0.01, corrected for multiple testing) demonstrating parallel expression changes are shown. Genes shown have the greatest changes in expression for both the NDAD vs. controls analysis and AD vs. controls analysis.

Fig. 2

Regional principal components analysis. Three principal components are shown for each region across healthy controls, NDAD brains, and AD brains (x-axis). The y-axis represents the logged normalized intensity value. The percentage of expression variance (across controls, NDAD, and AD brains) that each component accounts for is listed.

Fig. 3

RT-PCR validation of selected genes. RT-PCR validation of expression changes identified from array analysis was performed on unprofiled MTG (controls: n = 9, NDAD: n = 8, AD: n = 9) and PC (controls: n = 8, NDAD: n = 8, AD: n = 11) samples. RT-PCR data, along with respective array data, are shown (quantitative data is listed in Table 6). Fold values normalized to controls are shown on the y-axis and genes are listed on the x-axis.