HDAC inhibitor-dependent transcriptome and memory reinstatement in cognitive decline models.
Aging and increased amyloid burden are major risk factors for cognitive diseases such as Alzheimer's disease (AD). Effective therapies for these diseases are lacking. Here, we evaluated mouse models of age-associated memory impairment and amyloid deposition to study transcriptome and cell type-specific epigenome plasticity in the brain and peripheral organs. We determined that aging and amyloid pathology are associated with inflammation and impaired synaptic function in the hippocampal CA1 region as the result of epigenetic-dependent alterations in gene expression. In both amyloid and aging models, inflammation was associated with increased gene expression linked to a subset of transcription factors, while plasticity gene deregulation was differentially mediated. Amyloid pathology impaired histone acetylation and decreased expression of plasticity genes, while aging altered H4K12 acetylation-linked differential splicing at the intron-exon junction in neurons, but not nonneuronal cells. Furthermore, oral administration of the clinically approved histone deacetylase inhibitor vorinostat not only restored spatial memory, but also exerted antiinflammatory action and reinstated epigenetic balance and transcriptional homeostasis at the level of gene expression and exon usage. This study provides a systems-level investigation of transcriptome plasticity in the hippocampal CA1 region in aging and AD models and suggests that histone deacetylase inhibitors should be further explored as a cost-effective therapeutic strategy against age-associated cognitive decline.
Eva
E
Benito
Hendrik
H
Urbanke
Binu
B
Ramachandran
Jonas
J
Barth
Rashi
R
Halder
Ankit
A
Awasthi
Gaurav
G
Jain
Vincenzo
V
Capece
Susanne
S
Burkhardt
Magdalena
M
Navarro-Sala
Sankari
S
Nagarajan
Anna-Lena
AL
Schütz
Steven A
SA
Johnsen
Stefan
S
Bonn
Reinhardt
R
Lührmann
Camin
C
Dean
André
A
Fischer
D000107:Acetylation / Q000187:drug effects; D000375:Aging; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000682:Amyloid / Q000235:genetics / Q000378:metabolism; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008568:Memory / Q000187:drug effects*; D051379:Mice; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D000077337:Vorinostat
D000682:Amyloid; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D014157:Transcription Factors; D000077337:Vorinostat