Epigenetic regulation by G9a/GLP complex ameliorates amyloid‐beta 1‐42 induced deficits in long‐term plasticity and synaptic tagging/capture in hippocampal pyramidal neurons

Abstract

SummaryAltered 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.

MicroRNA‐134‐5p inhibition rescues long‐term plasticity and synaptic tagging/capture in an Aβ(1–42)‐induced model of Alzheimer’s disease

“…Hippocampal slices were then transferred onto the interface brain slice chamber (Scientific Systems Design) and incubated for three hours at 32°C with ACSF before the electrophysiology studies. Slices were treated with 200 nM Aβ (1–42) oligomers (Anaspec Inc) in a similar manner described in our previous reports (Krishna et al, ; Sharma et al, ) and 1 µM miR‐134 inhibitor (miR‐134i) oligonucleotide (AUM‐ANT‐A‐500 FANA miR‐134‐5p‐1 Inhibitor, AUM Biotech, LLC) or 1 µM scrambled miR‐134 inhibitor (FANA scrambled miR‐134 Inhibitor, AUM Biotech, LLC) at a flow rate of 1 ml/min of ACSF and 16 L/hr of carbogen for three hours during the incubation time. The entire process of animal dissection, hippocampal slice preparation and placement of slices on the chamber was done within approximately five minutes to ensure that hippocampal slices were in good condition for electrophysiology studies (Shetty et al, ).…”

“…In vitro oligomer preparation of Aβ (1–42) peptide (AnaSpec, Fremont) was carried out 24 hr before the start of the experiment as reported previously (Krishna et al, ; Sharma et al, ; Stine, Dahlgren, Krafft, & LaDu, ). Briefly, Aβ (1–42) peptide films prepared in hexafluoroisopropanol (HFIP) were stored at −20°C.…”

“…Alzheimer's disease (AD), one of the major neurodegenerative disorders characterized by progressive memory loss and cognitive impairment, is mainly caused by the accumulation of amyloid β peptide (Aβ) and neurofibrillary tangles (Chen et al, ; Hardy & Selkoe, ). Aβ type (1–42) has been identified as a primary cause for amyloid plaque formation, loss of neurons and synaptic failure in the hippocampus, leading to deficits in synaptic plasticity and memory (Chen et al, ; Selkoe & Hardy, ; Sharma, Dierkes, & Sajikumar, ; Sheng, Sabatini, & Südhof, ). Exogenous application of Aβ (1–42) impairs long‐term potentiation (LTP), a cellular correlate of memory and synaptic tagging/capture (STC), a model to study associative plasticity in the hippocampus (Jiang et al, ; Krishna, Behnisch, & Sajikumar, ; Lei et al, ; Ma et al, ; Sharma et al, ).…”

“…Aβ type (1–42) has been identified as a primary cause for amyloid plaque formation, loss of neurons and synaptic failure in the hippocampus, leading to deficits in synaptic plasticity and memory (Chen et al, ; Selkoe & Hardy, ; Sharma, Dierkes, & Sajikumar, ; Sheng, Sabatini, & Südhof, ). Exogenous application of Aβ (1–42) impairs long‐term potentiation (LTP), a cellular correlate of memory and synaptic tagging/capture (STC), a model to study associative plasticity in the hippocampus (Jiang et al, ; Krishna, Behnisch, & Sajikumar, ; Lei et al, ; Ma et al, ; Sharma et al, ). The STC model states that memory formation is an associative and time‐dependent process (Frey & Morris, ; Redondo & Morris, ).…”

“…BDNF has been shown to have a neuroprotective effect against the toxicity induced by Aβ peptides (Arancibia et al, ; Caccamo, Maldonado, Bokov, Majumder, & Oddo, ). Further, downregulation of CREB and BDNF expression is associated with AD conditions where plasticity is impaired (Pugazhenthi, Wang, Pham, Sze, & Eckman, ; Sharma et al, ). However, the key molecular mechanism regulating the expression of these PRPs in AD condition remains unclear and needs to be elucidated.…”