Lookup NU author(s): Dr Christopher Morris,
Professor Ian McKeith,
Emeritus Professor Robert Perry
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
Our hypothesis is that changes in gene and protein expression are crucial to the development of late-onset Alzheimer’s disease. Previously we examined how DNA alleles control downstream expression of RNA transcripts and how those relationships are changed in late-onset Alzheimer’s disease. We have now examined how proteins are incorporated into networks in two separate series and evaluated our outputs in two different cell lines. Our pipeline included the following steps: (i) predicting expression quantitative trait loci; (ii) determining differential expression; (iii) analysing networks of transcript and peptide relationships; and (iv) validating effects in two separate cell lines. We performed all our analysis in two separate brain series to validate effects. Our two series included 345 samples in the first set (177 controls, 168 cases; age range 65–105; 58% female; KRONOSII cohort) and 409 samples in the replicate set (153 controls, 141 cases, 115 mild cognitive impairment; age range 66–107; 63% female; RUSH cohort). Our top target is heat shock protein family A member 2 (HSPA2), which was identified as a key driver in our two datasets. HSPA2 was validated in two cell lines, with overexpression driving further elevation of amyloid-β40 and amyloid-β42 levels in APP mutant cells, as well as significant elevation of microtubule associated protein tau and phosphorylated-tau in a modified neuroglioma line. This work further demonstrates that studying changes in gene and protein expression is crucial to understanding late onset disease and further nominates HSPA2 as a specific key regulator of late-onset Alzheimer’s disease processes.10.1093/brain/awy215_video1awy215media15824729224001.
Author(s): Petyuk VA, Chang R, Ramirez-Restrepo M, Beckmann ND, Henrion MYR, Piehowski PD, Zhu K, Wang S, Clarke J, Huentelman MJ, Xie F, Andreev V, Engel A, Guettoche T, Navarro L, De Jager P, Schneider JA, Morris CM, McKeith IG, Perry RH, Lovestone S, Woltjer RL, Beach TG, Sue LI, Serrano GE, Lieberman AP, Albin RL, Ferrer I, Mash DC, Hulette CM, Ervin JF, Reiman EM, Hardy JA, Bennett DA, Schadt E, Smith RD, Myers AJ
Publication type: Article
Publication status: Published
Print publication date: 01/09/2018
Online publication date: 20/08/2018
Acceptance date: 22/06/2018
ISSN (print): 0006-8950
ISSN (electronic): 1460-2156
Publisher: Oxford University Press
PubMed id: 30137212
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