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000/SRR1696400/SRR1696400.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR169/006/SRR1696416/SRR1696416.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR169/000/SRR1696370/SRR1696370.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR169/007/SRR1696367/SRR1696367.fastq.gzprimaryOK200GenomicsAndre Fischer, Epigenetics of Aging, DZNE Goettingenhttps://www.ebi.ac.uk/ena/browser/view/PRJNA269577Mus musculusxref:PubMed:26280576Aging and increased amyloid burden are major risk factors for cognitive diseases such as Alzheimer's Disease (AD). An effective therapy does not yet exist. Here we use mouse models for age-associated memory impairment and amyloid deposition to study transcriptome and cell type-specific epigenome plasticity at the systems level in the brain and in peripheral organs. We show that at the level of epigenetic gene-expression aging and amyloid pathology are associated with inflammation and impaired synaptic function in the hippocampal CA1 region. While inflammation is associated with increased gene-expression that is linked to a subset of transcription factors, de-regulation of plasticity genes is mediated via different mechanisms in the amyloid and the aging model. Amyloid pathology impairs histone-acetylation and decreases expression of plasticity genes while aging affects differential splicing that is linked to altered H4K12 acetylation at the intron-exon junction in neurons but not in non-neuronal cells. We furthermore show that oral administration of the clinically approved histone deacetylase inhibitor Vorinostat not only restores spatial memory, but also exhibits an anti-inflammatory action and reinstates epigenetic balance and transcriptional homeostasis at the level of gene expression and exon usage. This is the first systems-level investigation of transcriptome plasticity in the hippocampal CA1 region in aging and AD models and of the effects of an orally dosed histone deacetylase inhibitor. Our data has important implications for the development of minimally invasive and cost-effective therapeutic strategies against age-associated cognitive decline. In fact, our data strongly suggest to test Vorinostat in patients suffering from AD. Overall design: mRNA profile from aged (CA1 and liver) and APP/PS1 (CA1) animals treated with oral vehicle or SAHA for 4 weeksENAAmyloid intracellular domain 57, APP, ABETA, Amyloid intracellular domain 59, PS, pres, DmelCG1771, Ad3h, alphaPS1, DmelCG42318, P3(40), DrosPS, metazoans, A4, CTFgamma, alpha-PS1, betaApp, animals, Amyloid intracellular domain 50, Abpp, CG11121, jecur, AAA, AID(59), AW555628, Cvap, region CA1, CG42318, old, AG, SABP3, carbonic anhydrase 1, Beta-amyloid protein 42, DmelCG11121, l(1)G0429, APP-C57, BETA CARBONIC ANHYDRASE 1, APP-C59, Beta-amyloid protein 40, CA1 field of the Ammon horn, Animal, ATSABP3, AID(50), field CA1, Animalia, Presenilin-1, somda, Ag, Dps, DPS, PreA4, F22O13.18, DmPS, iecur, S-APP-beta, Dmel_CG17144, CG5620, Gamma-CTF(59), SO, CG5868, Alzheimer disease amyloid A4 protein homolog, N-APP, AID(57), l(1)G0443, Gamma-secretase C-terminal fragment 50, mRNA-seq, Gamma-secretase C-terminal fragment 57, Gamma-secretase C-terminal fragment 59, ATBCA1, AD1, AD3, Ca1, Abeta, TG, APPI, C80, So, Drl, C83, Car-1, CA-I, Amyloidogenic glycoprotein, AICD-50, alpha[[PS1]], S-APP-alpha, E030013M08Rik, PS1, CG17144, F4P13_5, CR32097, Metazoa., Gamma-CTF(57), CA1 field of the hippocampus, S182, Mdu, aPS1, Gamma-CTF(50), C99, APP-C99, PSN, mda, Adap, Metazoa, AICD-57, CG1771, F22O13_18, PARALLEL SPINDLE 1, PS1alpha, ami, field CA1 of hippocampus, AICD-59, Cerebral vascular amyloid peptide, ATPS1, PS-1, P3(42), PN-II, DPsn, psn, med, alpha1Int, SALICYLIC ACID-BINDING PROTEIN 3, Soluble APP-beta, Alzheimer disease amyloid protein, Protease nexin-II, Dmel_CG5620, C31, CT5254, ARABIDOPSIS THALIANA SALICYLIC ACID-BINDING PROTEIN 3, multicellular animals, Livers, F4P13.5, CG18803, FAD, dPsn, l(3)77CDb, Soluble APP-alpha, PN2, Beta-APP42, Beta-APP40, DmelCG18803, PSalpha1, CVAP, Ammon's horn (Lorente de Ns), ABPPMus musculus, Laboratory Mice., House, Mus, Laboratory, Swiss, Mus domesticus, mouse, Mus musculus domesticus, Swiss Mouse, mouse <Mus musculus>, Mouse, House Mice, Swiss Mice, house mouse, Mice, Laboratory Mouse, House Mouse, mice C57BL/6xCBA/CaJ hybrid, domesticus, Mus muscarisfalseMus musculusmRNA-Seq of the CA1 hippocampal subregion and liver from 3 month and 20 month old animals treated orally with vehicle or SAHA and mRNA-Seq of CA1 of 10 month old WT or APP/PS1-21 transgenic animals treated orally with vehicle or SAHA2025-09-242015-08-18PRJNA269577GSE639431009026280576