Transcriptome Changes in the Alzheimer’s Disease Middle Temporal Gyrus: Importance of RNA Metabolism and Mitochondria-Associated Membrane Genes

Article type: Research Article

Authors: Piras, Ignazio S.^a | Krate, Jonida^{a; 1} | Delvaux, Elaine^b | Nolz, Jennifer^b | Mastroeni, Diego F.^b | Persico, Antonio M.^{c; d} | Jepsen, Wayne M.^a | Beach, Thomas G.^e | Huentelman, Matthew J.^a | Coleman, Paul D.^{b; *}

Affiliations: [a] Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA | [b] Biodesign Institute, Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, USA | [c] Unit of Child and Adolescent Neuropsychiatry, “Gaetano Martino” University Hospital, University of Messina, Messina, Italy | [d] Mafalda Luce Center for Pervasive Developmental Disorders, Milan, Italy | [e] Civin Laboratory of Neuropathology at Banner Sun Health Research Institute, Sun City, AZ, US

Correspondence: [*] Correspondence to: Paul D. Coleman, Biodesign Institute, Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ 85287, USA. E-mail: Paul.Coleman@asu.edu.

Note: [1] Current Institution: Department of Medicine, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA

Abstract: We used Illumina Human HT-12 v4 arrays to compare RNA expression of middle temporal gyrus (MTG; BA21) in Alzheimer’s disease (AD = 97) and non-demented controls (ND = 98). A total of 938 transcripts were highly differentially expressed (adj p < 0.01; log2 FC ≥ |0.500|, with 411 overexpressed and 527 underexpressed in AD. Our results correlated with expression profiling in neurons from AD and ND obtained by laser capture microscopy in MTG from an independent dataset (log2 FC correlation: r = 0.504; p = 2.2e-16). Additionally, selected effects were validated by qPCR. ANOVA analysis yielded no difference between genders in response to AD, but some gender specific genes were detected (e.g., IL8 and AGRN in males, and HSPH1 and GRM1 in females). Several transcripts were associated with Braak staging (e.g., AEBP1 and DNALI1), antemortem MMSE (e.g., AEBP1 and GFAP), and tangle density (e.g., RNU1G2, and DNALI1). At the pathway level, we detected enrichment of synaptic vesicle processes and GABAergic transmission genes. Finally, applying the Weighted Correlation Network Analysis, we identified four expression modules enriched for neuronal and synaptic genes, mitochondria-associated membrane, chemical stimulus and olfactory receptor and non-coding RNA metabolism genes. Our results represent an extensive description of MTG mRNA profiling in a large sample of AD and ND. These data provide a list of genes associated with AD, and correlated to neurofibrillary tangles density. In addition, these data emphasize the importance of mitochondrial membranes and transcripts related to olfactory receptors in AD.

Keywords: Alzheimer’s disease, microarray, middle temporal gyrus, postmortem brains, RNA profiling

DOI: 10.3233/JAD-181113

Journal: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 691-713, 2019