Epigenetic suppression of neuroligin 1 underlies amyloid-induced memory deficiency.
Amyloid-induced microglial activation and neuroinflammation impair central synapses and memory function, although the mechanism remains unclear. Neuroligin 1 (NLGN1), a postsynaptic protein found in central excitatory synapses, governs excitatory synaptic efficacy and plasticity in the brain. Here we found, in rodents, that amyloid fibril-induced neuroinflammation enhanced the interaction between histone deacetylase 2 and methyl-CpG-binding protein 2, leading to suppressed histone H3 acetylation and enhanced cytosine methylation in the Nlgn1 promoter region and decreased NLGN1 expression, underlying amyloid-induced memory deficiency. Manipulation of microglia-associated neuroinflammation modulated the epigenetic modification of the Nlgn1 promoter, hippocampal glutamatergic transmission and memory function. These findings link neuroinflammation, synaptic efficacy and memory, thus providing insight into the pathogenesis of amyloid-associated diseases.
1] Department of General Anesthesiology, Anesthesiology Institute, Cleveland Clinic, Cleveland, Ohio, USA. [2].
Bihua
B
Bie
1] Department of General Anesthesiology, Anesthesiology Institute, Cleveland Clinic, Cleveland, Ohio, USA. [2].
Jiang
J
Wu
Department of General Anesthesiology, Anesthesiology Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Hui
H
Yang
Department of General Anesthesiology, Anesthesiology Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Jijun J
JJ
Xu
Department of General Anesthesiology, Anesthesiology Institute, Cleveland Clinic, Cleveland, Ohio, USA.
David L
DL
Brown
Department of General Anesthesiology, Anesthesiology Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Mohamed
M
Naguib
D000682:Amyloid / Q000633:toxicity*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D019175:DNA Methylation; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D008569:Memory Disorders / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053764:Presenilin-1 / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D015816:Cell Adhesion Molecules, Neuronal; D018691:Excitatory Amino Acid Antagonists; D008070:Lipopolysaccharides; D051783:Methyl-CpG-Binding Protein 2; C508853:PSEN1 protein, human; D053764:Presenilin-1; C093438:neuroligin 1; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2