We present a consensus atlas of the human brain transcriptome in Alzheimer's disease (AD), based on meta-analysis of differential gene expression in 2,114 postmortem samples. We discover 30 brain coexpression modules from seven regions as the major source of AD transcriptional perturbations. We next examine overlap with 251 brain differentially expressed gene sets from mouse models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus tau pathology and reveal age- and sex-dependent expression signatures for disease progression. Human coexpression modules enriched for neuronal and/or microglial genes broadly overlap with mouse models of AD, Huntington's disease, amyotrophic lateral sclerosis, and aging. Other human coexpression modules, including those implicated in proteostasis, are not activated in AD models but rather following other, unexpected genetic manipulations. Our results comprise a cross-species resource, highlighting transcriptional networks altered by human brain pathophysiology and identifying correspondences with mouse models for AD preclinical studies.
Wan YW, Al-Ouran R, Mangleburg CG, Perumal TM, Lee TV, Allison K, Swarup V, Funk CC, Gaiteri C, Allen M, Wang M, Neuner SM, Kaczorowski CC, Philip VM, Howell GR, Martini-Stoica H, Zheng H, Mei H, Zhong X, Kim JW, Dawson VL, Dawson TM, Pao PC, Tsai LH, Haure-Mirande JV, Ehrlich ME, Chakrabarty P, Levites Y, Wang X, Dammer EB, Srivastava G, Mukherjee S, Sieberts SK, Omberg L, Dang KD, Eddy JA, Snyder P, Chae Y, Amberkar S, Wei W, Hide W, Preuss C, Ergun A, Ebert PJ, Airey DC, Mostafavi S, Yu L, Klein HU, , Carter GW, Collier DA, Golde TE, Levey AI, Bennett DA, Estrada K, Townsend TM, Zhang B, Schadt E, De Jager PL, Price ND, Ertekin-Taner N, Liu Z, Shulman JM, Mangravite LM, Logsdon BA. (2020). Meta-Analysis of the Alzheimer's Disease Human Brain Transcriptome and Functional Dissection in Mouse Models. Cell reports, 32(2)