Increased EID1 nuclear translocation impairs synaptic plasticity and memory function associated with pathogenesis of Alzheimer's disease

Abstract

Though loss of function in CBP/p300, a family of CREB-binding proteins, has been causally associated with a variety of human neurological disorders, such as Rubinstein-Taybi syndrome, Huntington’s disease and drug addiction, the role of EP300 interacting inhibitor of differentiation 1 (EID1), a CBP/p300 inhibitory protein, in modulating neurological functions remains completely unknown. Through the examination of EID1 expression and cellular distribution, we discovered that there is a significant increase of EID1 nuclear translocation in the cortical neurons of Alzheimer’s disease (AD) patient brains compared to that of control brains. To study the potential effects of EID1 on neurological functions associated with learning and memory, we generated a transgenic mouse model with a neuron-specific expression of human EID1 gene in the brain. Overexpression of EID1 led to an increase in its nuclear localization in neurons mimicking that seen in human AD brains. The transgenic mice had a disrupted neurofilament organization and increase of astrogliosis in the cortex and hippocampus. Furthermore, we demonstrated that overexpression of EID1 reduced hippocampal long-term potentiation and impaired spatial learning and memory function in the transgenic mice. Our results indicated that the negative effects of extra nuclear EID1 in transgenic mouse brains are likely due to its inhibitory function on CBP/p300 mediated histone and p53 acetylation, thus affecting the expression of downstream genes involved in the maintenance of neuronal structure and function. Together, our data raise the possibility that alteration of EID1 expression, particularly the increase of EID1 nuclear localization that inhibits CBP/p300 activity in neuronal cells, may play an important role in AD pathogenesis.

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…Interestingly, the authors showed that the neuron-specific expression of human EID1 gene in a mouse model reduced hippocampal LTP and impaired spatial memory. This phenotype was associated with the hypo-acetylation of histone H3 and p53 [157]. This study also confirmed an association between CBP activity deregulation and human pathology.…”

“…Therefore, increasing CBP activity might be an interesting therapeutic tool in this case. In addition, an endogenous inhibitor of p300/CBP (EP300-interacting inhibitor of differentiation 1 or EID1) was shown to translocate from the cytoplasm to the nucleus in the hippocampus of the brain of an AD patient [157]. Interestingly, the authors showed that the neuron-specific expression of human EID1 gene in a mouse model reduced hippocampal LTP and impaired spatial memory.…”

The Role of Histone Acetylation in Memory Formation and Cognitive Impairments

“…This ability is disrupted in the AD mutant variants (Francis et al, 2007;Francis et al, 2006) implicating abnormal CBP/p300-mediated gene expression in the molecular basis of AD pathology. Nuclear localization of p300 interacting inhibitor of differentiation 1 (EID1), a CBP/p300 inhibitory protein, has also been shown to play a role in AD pathogenesis (Liu et al, 2012). Systemic injection of HDAC inhibitors is able to rescue age-dependent memory deficits in a mouse model of AD (Kilgore et al, 2010).…”

Epigenetics of Brain Disorders: The Paradigm of Alzheimer ’s Disease

“…Histone modifications are present in AD [9,15,16,63,73] ; (ix) nuclear translocation of EP300 interacting inhibitor of differentiation 1 (EID1), a CBP/p300 inhibitory protein, is increased in the cortical neurons of AD patients, and overexpression of EID1 is reported to reduce hippocampal LTP and to impair cognitive function via inhibiting CBP/p300 acetyl trasferase activity and disrupting neuronal structure [83]; (x) memory formation leads to a transient increase in acetylation on lysine residues within H2B, H3, H4 [84,85]; (xi) inhibition of HDAC induces dendritic sprouting, increases synaptic number, and improves long-term memory [86]; (xii) overexpression of neuronal HDAC2 decreases dendritic spine density, synapse number, synaptic plasticity and memory formation, and HDAC2 deficiency increases synapse number and memory facilitation [87,88]; (xiii) HDAC4 is involved in learning and synaptic plasticity, and selective inhibition of HDAC4 activity may deteriorate learning and memory [89]; (xiv) treatment of hippocampal neurons with HDAC inhibitors facilitates Bdnf expression via hyper acetylation of histones at the Bdnf promoters [90,91]; (xv) histone(H3K4) methylation participates in the regulation of Bdnf expression and memory formation [92]; (xvi) histone methylation also facilitates memory consolidation coupled with histone acetylation; inhibition of HDACs with sodium butyrate (NaB) causes an increase in H3K4 trimethylation and a decrease in H3K9 dimethylation in the hippocampus after fear conditioning [92]; (xvii) histone H3 acetylation, methylation and phosphorylation is increased in the prefrontal cortex of Tg2576 mice, and histone H4 acetylation is increased in the hippocampal CA1 neurons of these transgenic mice [15,16,93].…”

“…Histone modifications are present in AD [9,15,16,63,73]: (i) histone acetylation is reduced in AD brain tissues [74] and in AD transgenic models [63]; (ii) levels of HDAC6, a tau-interacting protein and a potential modulator of tau phosphorylation and accumulation, are increased in cortical and hippocampal regions in AD [75]; (iii) SIRT1 is decreased in the parietal cortex of AD patients, and the accumulation of Aβ and tau in AD brains might be related to the loss of SIRT1 [76], since SIRT1 may reduce Aβ production, activating the transcription of ADAM10 [77]; (iv) in the brains of twins discordant for AD, tri methylation of H3K9, a marker of gene silencing, and condensation of heterochromatin structure, are increased in the temporal cortex and hippocampus of the AD twin as compared to the twin devoid of AD neuropathology [78]; (v) phosphorylation of H3S10, a key regulator in chromatin compaction during cell division, is increased in the cytoplasm of hippocampal neurons in AD cases [79]; (vi) evidence of DNA damage, as reflected by phosphorylated H2AX at Ser139, is present in hippocampal astrocytes of AD patients [80]; (vii) long-term potentiation (LTP) and memory deficits in APP/PS1 transgenic mice might be mediated in part by decreased H4 acetylation; improving histone acetylation level restores learning after synaptic dysfunction [81]; (viii) acetylation of H3 and H4 is increased in 3xTg-AD neurons relative to non-transgenic neurons [82]; (ix) nuclear translocation of EP300 interacting inhibitor of differentiation 1 (EID1), a CBP/p300 inhibitory protein, is increased in the cortical neurons of AD patients, and overexpression of EID1 is reported to reduce hippocampal LTP and to impair cognitive function via inhibiting CBP/p300 acetyl trasferase activity and disrupting neuronal structure [83]; (x) memory formation leads to a transient increase in acetylation on lysine residues within H2B, H3, H4 [84,85]; (xi) inhibition of HDAC induces dendritic sprouting, increases synaptic number, and improves long-term memory [86]; (xii) overexpression of neuronal HDAC2 decreases dendritic spine density, synapse number, synaptic plasticity and memory formation, and HDAC2 deficiency increases synapse number and memory facilitation [87,88]; (xiii) HDAC4 is involved in learning and synaptic plasticity, and selective inhibition of HDAC4 activity may deteriorate learning and memory [89]; (xiv) treatment of hippocampal neurons with HDAC inhibitors facilitates Bdnf exp...…”