Selective neuronal vulnerability in Alzheimer’s disease: a network-based analysis

Roussarie, J.-P.; Yao, V.; Plautz, Z.; Kasturia, S.; Albornoz, C.; Schmidt, E. F.; Brichta, L.; Barnea-Cramer, A.; Heintz, N.; Hof, P.; Heiman, M.; Flajolet, M.; Troyanskaya, O.; Greengard, P.

doi:10.1101/499897

bioRxiv · 10.1101/499897

Selective neuronal vulnerability in Alzheimer’s disease: a network-based analysis

Roussarie, J.-P.·Yao, V.·Plautz, Z.·Kasturia, S.·Albornoz, C.·Schmidt, E. F.·Brichta, L.·Barnea-Cramer, A.·Heintz, N.·Hof, P.·Heiman, M.·Flajolet, M.·Troyanskaya, O.·Greengard, P.

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Abstract

A major obstacle to treating Alzheimers disease (AD) is our lack of understanding of the molecular mechanisms underlying selective neuronal vulnerability, which is a key characteristic of the disease. Here we present a framework to integrate high-quality neuron-type specific molecular profiles across the lifetime of the healthy mouse, which we generated using bacTRAP, with postmortem human functional genomics and quantitative genetics data. We demonstrate human-mouse conservation of cellular taxonomy at the molecular level for AD vulnerable and resistant neurons, identify specific genes and pathways associated with AD pathology, and pinpoint a specific functional gene module underlying selective vulnerability, enriched in processes associated with axonal remodeling, and affected by both amyloid accumulation and aging. Overall, our study provides a molecular framework for understanding the complex interplay between A{beta}, aging, and neurodegeneration within the most vulnerable neurons in AD.

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Roussarie, J.-P., Yao, V., Plautz, Z., Kasturia, S., Albornoz, C., Schmidt, E. F., Brichta, L., Barnea-Cramer, A., Heintz, N., Hof, P., Heiman, M., Flajolet, M., Troyanskaya, O., Greengard, P.. 2018-12-19. Selective neuronal vulnerability in Alzheimer’s disease: a network-based analysis. https://doi.org/10.1101/499897

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