Epigenetic regulation of HDAC1 SUMOylation as an endogenous neuroprotection against Aβ toxicity in a mouse model of Alzheimer’s disease

Abstract

Amyloid-β (Aβ) produces neurotoxicity in the brain and causes neuronal death, but the endogenous defense mechanism that is activated on Aβ insult is less well known. Here we found that acute Aβ increases the expression of PIAS1 and Mcl-1 via activation of MAPK/ERK, and Aβ induction of PIAS1 enhances HDAC1 SUMOylation in rat hippocampus. Knockdown of PIAS1 decreases endogenous HDAC1 SUMOylation and blocks Aβ induction of Mcl-1. Sumoylated HDAC1 reduces it association with CREB, increases CREB binding to the Mcl-1 promoter and mediates Aβ induction of Mcl-1 expression. Transduction of SUMO-modified lenti-HDAC1 vector to the hippocampus of APP/PS1 mice rescues spatial learning and memory deficit and long-term potentiation impairment in APP/PS1 mice. It also reduces the amount of amyloid plaque and the number of apoptotic cells in CA1 area of APP/PS1 mice. Meanwhile, HDAC1 SUMOylation decreases HDAC1 binding to the neprilysin promoter. These results together reveal an important role of HDAC1 SUMOylation as a naturally occurring defense mechanism protecting against Aβ toxicity and provide an alternative therapeutic strategy against AD. Cell Death and Differentiation (2017) 24, 597-614; doi:10.1038/cdd.2016.161; published online 10 February 2017The brain of Alzheimer's disease (AD) patient is characterized by the accumulation of senile plaques, and amyloid-β peptides (Aβ 1-40 and Aβ 1-42 ) are the major components of these senile plaques. Aβ is known to cause lipid peroxidation, free radical production, caspase 3 activation and DNA damage that eventually lead to neuronal death. [1][2][3] In addition, the Aβ peptide or overexpression of Aβ causes cognitive impairment in animals. 4,5 This cognitive impairment correlates with amyloid plaque formation 4,6 or precedes it. 7,8 Further, naturally secreted Aβ or the Aβ peptide also inhibits longterm potentiation (LTP) in the hippocampus in vivo and disrupts synaptic and network function. 9,10 More recently, we have found that Aβ induces the expression of activated signal transducer and activator of transcription-1 (STAT1) and Aβ induction of STAT1 mediates the memory-impairing effect of Aβ. 11 On the other hand, it is conceivable that when Aβ produces its toxicity, neurons would develop defense mechanisms to cope with Aβ toxicity. For example, a nonamyloidogenic neurotrophic peptide sAPPα is shown to activate neuroprotectin D1 and promote cell survival. 12 In addition, we have found that Aβ activates the MAPK/ERK-SGK (serum-and glucocorticoid-inducible kinase) signaling pathway for neuroprotection against Aβ insult. 13 However, with the role and mechanism of Aβ-induced toxicity been studied extensively, the endogenous protection mechanism induced by Aβ is less well known.Histone acetylation is one kind of epigenetic regulations that has an important role in a wide range of brain functions and disorders, and histone deacetylases (HDACs) regulate the homeostasis of histone acetylation. The HDAC family contains 18 HDAC proteins that belong to different classifications. Inhibitio...

HDAC1 SUMOylation promotes Argonaute directed transcriptional silencing inC. elegans

“…Our finding that conjugating SUMO to HDA-1(KKRR), by precision genome editing at the endogenous hda-1 locus in the worm, rescues both its piRNA silencing and fertility phenotypes lends credence to the possible physiological importance of HDAC1 SUMOylation in this Alzheimer's model. Taken together our worm studies and these studies in mammalian systems point to the likely importance of HDAC1 SUMOylation in the regulation of gene expression, and appear to validate the 'SUMO-complementation by gene-fusion' strategy employed here and previously by Tao et al, (2017).…”

“…While all of these studies revealed changes consistent with the likely importance of these residues in promoting HDAC1 functions, only one study explored whether appending SUMO to HDAC1 by translational fusion had opposing effects. Remarkably, this study showed that a lenti-virus driven of an HDAC1::SUMO fusion protein rescued the learning and memory deficits of an APP/Presenilin 1 murine model of Alzheimer's disease (Tao et al, 2017). Our finding that conjugating SUMO to HDA-1(KKRR), by precision genome editing at the endogenous hda-1 locus in the worm, rescues both its piRNA silencing and fertility phenotypes lends credence to the possible physiological importance of HDAC1 SUMOylation in this Alzheimer's model.…”

Neuroligin-1 is altered in the hippocampus of Alzheimer’s disease patients and mouse models, and modulates the toxicity of amyloid-beta oligomers

“…This could suggest that the negative impact on NLGN1 could play a role in GABAergic synapse dysfunctions observed in AD and animal models 68,69 , as well as in glutamatergic synapse modifications 8,12,21 . Besides, the initial increase in Nlgn1 expression after 2 days of Aβo exposure might belong to a neuroprotective pathway similar to other pathways driven by Aβ in the hippocampus 70 . NLGN1 was already shown to protect against oxidative stress in a non-mammalian model 71 and to express neuroprotective functions in hippocampal neurons 38,72 .…”

Cdk5-Mcl-1 axis promotes mitochondrial dysfunction and neurodegeneration in Alzheimer's disease model

“…A recent study revealed that β-amyloid injection into the lateral ventricles of mice results in downregulation of Mcl-1 due to a decrease in the levels of myocardin-related transcription factor-A (MRTF-A, also known as Mkl1), a transcriptional activator of Mcl-1 (Zhang et al, 2016). By contrast, another recent study reported that injection of β-amyloid in mice upregulates Mcl-1 mRNA leading to neuroprotection (Tao et al, 2017). Similarly, preconditioning of neurons with a sublethal dose of 5-aminoimidazole-4-carboxamide riboside (AICAR), activates AMP-activated protein kinase (AMPK), which in turn upregulates the transcription of Mcl-1, providing neuroprotection (Anilkumar et al, 2013).…”