Date Published: June 30, 2017
Publisher: John Wiley and Sons Inc.
Author(s): Mahima Sharma, Tobias Dierkes, Sreedharan Sajikumar.
Altered epigenetic mechanisms are implicated in the cognitive decline associated with neurodegenerative diseases such as in Alzheimer’s disease (AD). AD is the most prevalent form of dementia worldwide; amyloid plaques and neurofibrillary tangles are the histopathological hallmarks of AD. We have recently reported that the inhibition of G9a/GLP complex promotes long‐term potentiation (LTP) and its associative mechanisms such as synaptic tagging and capture (STC). However, the role of this complex in plasticity impairments remains elusive. Here, we investigated the involvement of G9a/GLP complex in alleviating the effects of soluble Amyloid‐β 1‐42 oligomers (oAβ) on neuronal plasticity and associativity in the CA1 region of acute hippocampal slices from 5‐ to 7‐week‐old male Wistar rats. Our findings demonstrate that the regulation of G9a/GLP complex by inhibiting its catalytic activity reverses the amyloid‐β oligomer‐induced deficits in late‐LTP and STC. This is achieved by releasing the transcription repression of the brain‐derived neurotrophic factor (Bdnf) gene. The catalytic inhibition of G9a/GLP complex leads to the upregulation of Bdnf expression in the slices treated with oAβ. This further ensures the availability of BDNF that subsequently binds its receptor tyrosine kinase B (TrkB) and maintains the late‐LTP. Furthermore, the capture of BDNF by weakly activated synapses re‐establishes STC. Our findings regarding the reinstatement of functional plasticity and associativity in AD‐like conditions provide the first evidence for the role of G9a/GLP complex in AD. We propose G9a/GLP complex as the possible target for preventing oAβ‐induced plasticity deficits in hippocampal neurons.
Epigenetic regulation plays a critical role in the process of learning and memory (Day & Sweatt, 2011; Jarome & Lubin, 2014), and dysregulation of these mechanisms underlies cognitive decline associated with neurodegenerative diseases such as Alzheimer’s disease (AD) (Cacabelos & Torrellas, 2015; Maloney & Lahiri, 2016). Various epigenetic alterations have been identified in AD (Cadena‐del‐Castillo et al., 2014; Cacabelos & Torrellas, 2015; Grinan‐Ferre et al., 2016; Klein et al., 2016). Higher levels of DNA methylation and DNA hydroxymethylation are reported in different mouse models of AD (Cadena‐del‐Castillo et al., 2014; Cong et al., 2014). HDAC inhibitors exert a protective effect in AD (Klein et al., 2015; Krishna et al., 2016), indirectly suggesting the importance of regulation of histone acetylation during the cognitive decline. Histone methylation is thought to play an important role in AD as well. The G9a/GLP complex, along with other enzymes, regulating this histone modification is widely implicated in learning and memory processes (Schaefer et al., 2009; Maze et al., 2010; Fischer, 2014). The G9a/GLP complex is a histone lysine‐methyltransferase complex that predominantly dimethylates lysine 9 residue of Histone 3 (H3K9me2) (Tachibana et al., 2005). Catalytic inhibition of this epigenetic complex was recently reported to promote long‐term potentiation (LTP), a cellular correlate of memory and its associative mechanisms such as synaptic tagging and capture (STC) (Sharma et al., 2016). However, the role of this complex in plasticity impairment still remains elusive.
Dysregulation of epigenetic mechanisms is one of the major factors responsible for cognitive decline during aging and neurodegenerative diseases such as Alzheimer’s disease (AD) (Cacabelos & Torrellas, 2015; Maloney & Lahiri, 2016). Substantial research has focused on rescuing the cognitive deficit during AD by regulating the histone acetylation in AD mouse models and in vitro studies (Cacabelos & Torrellas, 2015; Klein et al., 2015; Grinan‐Ferre et al., 2016; Krishna et al., 2016). Epigenetic regulation by G9a/GLP histone lysine–methyltransferase complex is emerging as a critical mechanism underlying the learning and memory processes (Schaefer et al., 2009; Maze et al., 2010; Gupta‐Agarwal et al., 2012). Our present findings confirm that inhibiting the catalytic activity of G9a/GLP complex is beneficial in restoring the late‐phase of LTP that is otherwise impaired by Aβ 1–42 oligomer (oAβ). The abrogation of late‐LTP by oAβ is consistent with previous studies (Ma et al., 2014; Lei et al., 2016). The synthesis of plasticity proteins, which is disrupted by Aβ 1–42 (Chen et al., 2002), is required for the maintenance phase of LTP (Frey et al., 1988; Pang & Lu, 2004). Restoring the protein synthesis capability of a neuronal population is therefore a plausible way to ameliorate the Aβ‐induced synaptic deficits. We demonstrate that rescue of oAβ‐induced LTP deficit by catalytic inhibition of G9a/GLP complex is indeed protein synthesis and NMDA receptor dependent, thus representing a physiological correlate of memory (Lynch, 2004).
S.S. is supported by National Medical Research Council Collaborative Research Grant (NMRC/CBRG/0041/2013 and NMRC/CBRG/0099/2015) and NUS‐Strategic and Aspiration Research Funds. The funding agency had no role in design of experiments or its interpretation. M.S. is supported by President Graduate Fellowship, National University of Singapore.