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. 2020 Aug 15;23(9):101465. doi: 10.1016/j.isci.2020.101465

Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease

Margaret O'Connor 1,6, Yang-Ping Shentu 2,3,6, Guan Wang 1, Wen-Ting Hu 2, Zhen-Dong Xu 2, Xiao-Chuan Wang 2, Rong Liu 2,∗, Heng-Ye Man 1,4,5,7,∗∗
PMCID: PMC7476873  PMID: 32861999

Summary

In Alzheimer's disease (AD), decreases in the amount and synaptic localization of AMPA receptors (AMPARs) result in weakened synaptic activity and dysfunction in synaptic plasticity, leading to impairments in cognitive functions. We have previously found that AMPARs are subject to lysine acetylation, resulting in higher AMPAR stability and protein accumulation. Here we report that AMPAR acetylation was significantly reduced in AD and neurons with Aβ incubation. We identified p300 as the acetyltransferase responsible for AMPAR acetylation and found that enhancing GluA1 acetylation ameliorated Aβ-induced reductions in total and cell-surface AMPARs. Importantly, expression of acetylation mimetic GluA1 (GluA1-4KQ) in APP/PS1 mice rescued impairments in synaptic plasticity and memory. These findings indicate that Aβ-induced reduction in AMPAR acetylation and stability contributes to synaptopathy and memory deficiency in AD, suggesting that AMPAR acetylation may be an effective molecular target for AD therapeutics.

Subject Areas: Behavioral Neuroscience, Molecular Neuroscience, Cellular Neuroscience

Graphical Abstract

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Highlights

  • •

    AMPAR acetylation is reduced in AD brain and neurons with Aβ incubation

  • •

    p300 is the acetyltransferase for AMPAR acetylation

  • •

    Up-regulation of AMPAR acetylation in neurons blocks Aβ-induced receptor internalization

  • •

    Expression of GluA1 acetylation mimetic rescues cognitive deficits in APP/PS1 mice

Behavioral Neuroscience; Molecular Neuroscience; Cellular Neuroscience

Introduction

Alzheimer's disease (AD) is the most common form of dementia characterized by impairments in learning and memory. A key hallmark of AD is the accumulation of amyloid-β (Aβ), which has been shown to cause loss of dendritic spines and dysregulation in synaptic functions, such as basal transmission and synaptic plasticity (Forner et al., 2019; Palop and Mucke, 2010; Rajmohan and Reddy, 2017; Selkoe, 2002; Sheng et al., 2012; Yu and Lu, 2012). Evidence suggests these impairments in synaptic function are an early pathology, which ultimately lead to the cognitive failures observed in AD (Baglietto-Vargas et al., 2018; Chen et al., 2000; Li et al., 2011; Ma and Klann, 2012; Oddo et al., 2003; Selkoe and Hardy, 2016).

AMPA receptors (AMPARs) mediate most of the excitatory synaptic transmission that underlies higher brain functions, including learning and memory. A change in the synaptic expression of AMPARs is the key mechanism underlying synaptic plasticity, the molecular basis for learning and memory. An increase in surface AMPARs through exocytosis leads to the expression of long-term potentiation (LTP), whereas internalization of AMPARs causes long-term depression (LTD) (Chidambaram et al., 2019; Collingridge et al., 2004; Derkach et al., 2007; Ju and Zhou, 2018; Kopec et al., 2006; Lledo et al., 1998; Lüscher et al., 1999; Makino and Malinow, 2009; Malinow and Malenka, 2002; Shepherd and Huganir, 2007; Song and Huganir, 2002). Consistent with impairments in synaptic function, a reduction in AMPARs has been observed in the brains of both human patients with AD and mouse models of AD (Armstrong et al., 1994; Cantanelli et al., 2014; Carter et al., 2004; Chang et al., 2006; D'Amelio et al., 2011; Dewar et al., 1991; Du et al., 2020; Gao et al., 2016; Gong et al., 2009; Jacob et al., 2007; Monteiro-Fernandes et al., 2020; Samra and Ramtahal, 2012; Thorns et al., 1997; Wakabayashi et al., 1999; Yasuda et al., 1995). In line with this, incubation of neurons with Aβ results in down-regulation in AMPAR amounts (Guntupalli et al., 2016; Miyamoto et al., 2016; Parameshwaran et al., 2008; Thomas et al., 2017; Wisniewski et al., 2011; Yu and Lu, 2012; Zhang et al., 2018).

The abundance of AMPARs in the post-synaptic domain is regulated by dynamic receptor trafficking. Enhanced receptor internalization and an ultimate reduction in AMPAR synaptic accumulation has been shown to be an early pathological feature of AD (Almeida et al., 2005; Baglietto-Vargas et al., 2018; Hsieh et al., 2006; Li et al., 2019; Zhao et al., 2010). Overexpression of amyloid precursor protein (APP) or application of soluble oligomeric Aβ results in a reduction in surface expression of AMPARs (Alfonso et al., 2014; Gu et al., 2009; Miller et al., 2014; Roselli et al., 2005; Tanaka et al., 2019; Zhang et al., 2011) likely due to endocytosis of AMPARs from the synaptic surface (Hsieh et al., 2006; Miñano-Molina et al., 2011; Wang et al., 2011; Zhang et al., 2017). The reduced stability of AMPARs may be a major contributing factor to the pathology of AD.

In AD, the reduction in AMPAR seems to result from reduced receptor stability. Indeed, treatment with Aβ increased AMPAR mobility (Opazo et al., 2018) and, in the presence of cycloheximide, shortened AMPAR half-life (Zhang et al., 2018). Studies have demonstrated that ubiquitination is a primary regulatory mechanism contributing to AMPAR stability (Guntupalli et al., 2017; Rodrigues et al., 2016; Zhang et al., 2018). AMPARs are subject to ubiquitination via the E3 ligase Nedd4 (Hou et al., 2011; Lin et al., 2011; Rodrigues et al., 2016; Schwarz et al., 2010) and deubiquitination by the deubiquitinase USP46 (Huo et al., 2015). Plasma membrane-inserted AMPARs are preferentially targeted for ubiquitination (Lin et al., 2011), leading to receptor internalization and subsequent proteasomal degradation (Goo et al., 2015; Hou et al., 2011; Jarzylo and Man, 2012; Zhang et al., 2009).

We have recently demonstrated that AMPARs are also subject to lysine acetylation, a regulation that competes with ubiquitination because both processes target lysine residues. Acetylation confers AMPARs with higher levels of stability due to a suppression in AMPAR internalization and degradation (Wang et al., 2017). We have shown that inhibition of the AMPAR deacetylase, SIRT2, causes enhanced AMPAR acetylation and increased AMPAR accumulation at synapses (Wang et al., 2017). Because AMPAR reduction is a crucial first step leading to the cognitive deficits in AD, restoration of AMPARs at the synapse is predicted to improve synaptic strength and cognitive function in AD.

In this study, we find that AMPAR acetylation is altered under AD conditions. In Aβ-incubated neurons, and in brains of transgenic AD mice and patients with AD, AMPARs show marked reduction in acetylation. We show that up-regulation of AMPAR acetylation leads to a suppression in AMPAR internalization and an increase in total AMPAR amount. We identify p300 as the acetyltransferase responsible for AMPAR acetylation and find that activation of p300, or inhibition of AMPAR deacetylase SIRT2, results in an increase in AMPAR acetylation and blocks the Aβ-induced reduction in surface AMPAR expression. Importantly, we found that hippocampal expression of an acetylation mimetic GluA1 was able to restore synaptic plasticity and rescue cognitive deficits in the Tg (APPswe, PSEN1dE9)85Dbo (APP/PS1) mouse model. Together, these findings provide insights into the importance of AMPAR acetylation in the pathogenesis of cognitive dysfunction in AD.

Results

Aβ Induces a Reduction in AMPAR Acetylation

Our studies and the work of others have shown that AMPAR levels are reduced in AD (Armstrong et al., 1994; Carter et al., 2004; Dewar et al., 1991; Gong et al., 2009; Thorns et al., 1997; Yasuda et al., 1995; Zhang et al., 2018). In AD brains and Aβ-treated neurons, ubiquitination of AMPARs is up-regulated (Guntupalli et al., 2017; Rodrigues et al., 2016; Zhang et al., 2018), and studies have demonstrated proteasomal degradation of ubiquitinated AMPARs (Huo et al., 2015; Jarzylo and Man, 2012; Lin et al., 2011). Recently, we found that AMPARs are subject to another form of protein modification, i.e., acetylation, a modification that opposes receptor ubiquitination and functions to stabilize AMPARs (Wang et al., 2017). We therefore wondered whether this modification of AMPARs is altered in AD conditions, contributing to the aberrance in receptor expression. To this end, we first used immunostaining to confirm the effect of Aβ oligomers on the abundance of AMPAR expression. DIV 15 cultured rat hippocampal neurons were treated with Aβ (1 μM) for 24 h and labeled with specific antibodies against AMPAR subunit GluA1. Immunostaining against the GluA1 N terminus under non-permeant conditions showed a reduction in the intensity of surface GluA1 puncta, and antibodies against the GluA1 C terminus under permeant conditions showed a similar reduction in total levels of GluA1 (Figures 1A and 1B). To examine specifically the expression level of AMPARs at the synaptic sites, we purified synaptosomes from cultured cortical neurons. We found that the Aβ treatment resulted in a 62% reduction in the amount of GluA1 in the synaptosome, comparable with an overall 65% reduction from total cell lysate (Figures 1C and 1D). In addition, we found that Aβ treatment did not affect the levels of PSD95 (Figure 1E). These findings indicate that Aβ incubation leads to a down-regulation of synaptic AMPARs in neurons.

Figure 1.

Figure 1

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Aβ Treatment Induces a Reduction in AMPAR Acetylation

(A) Hippocampal neurons were treated with Aβ (1 μM) for 24 h and probed for synaptic GluA1 using immunocytochemistry (Total GluA1, green; Surface GluA1, red) (scale bar, 5 μm).

(B) Quantitative analysis of the GluA1 puncta intensity showed a decrease in both surface and total intensities (Ctrl, n = 10 cells, 548 puncta; Aβ, n = 11 cells, 511 puncta).

(C) Synaptosome purification of cultured cortical neurons incubated with Aβ (n = 3 experiments).

(D) Quantification showed a decrease in synaptically localized, as well as total, GluA1 levels.

(E) Quantification shows no change in PSD95 levels.

(F) GluA1 acetylation levels were assessed via acetylation assays using cultured cortical neurons incubated with Aβ (n = 4 experiments).

(G) Quantitative analysis showed that application of Aβ reduced acetylated and total GluA1 levels. GluA1 acetylation was measured by normalizing the acetyl-lysine signal to the amount of GluA1 in IP.

(H) Quantification shows no change in PSD95 levels.

(I) Acetylation assays from prefrontal cortical brain homogenates from AD patient and healthy control brains (n = 3 brains).

(J) Quantification showed reduced acetylation of GluA1 in AD patients' brains compared with those of controls.

(K) Quantification showed a significant increase in GluA1 ubiquitination in AD brains compared with those of controls.

∗p<0.05, ∗∗p<0.01. Data are mean ± SEM.

We wondered whether AMPAR acetylation plays a role in Aβ-induced AMPAR down-regulation. Using DIV 15 primary cortical neurons treated with Aβ (1 μM) for 24 h, we isolated AMPAR GluA1 subunits via immunoprecipitation and probed western blots with antibodies specific for lysine acetylation (Inuzuka et al., 2012; Wang et al., 2017). We found that, compared with the control, incubation with Aβ resulted in a significant reduction in acetylation signal in precipitated GluA1 (Figures 1F and 1G). There was no significant difference in PSD95 levels (Figure 1H). To further determine the state of AMPAR acetylation in AD, we examined lysates from postmortem AD patient brains. GluA1 was precipitated from the prefrontal cortex lysates from patients and healthy controls. In line with our findings from Aβ-treated neurons, the AD patient brain homogenates showed a consistent decrease in the extent of GluA1 acetylation compared with the non-AD controls (Figures 1I and 1J). We also observed a dramatic increase in GluA1 ubiquitination (Figure 1K). Together these results demonstrate that AMPAR acetylation is decreased in vitro in Aβ-treated neurons and ex vivo in human AD brains.

The Acetyltransferase p300 Causes GluA1 Acetylation

Our previous work has identified SIRT2 as the deacetylase responsible for the deacetylation of GluA1 (Wang et al., 2017); however, the enzyme(s) responsible for AMPAR acetylation remains unknown. We therefore sought to identify the acetyltransferase that catalyzes the conjugation of the acetyl group to the lysine residues at GluA1 C terminus (GluA1ct). To this end, we purified GST-tagged GluA1ct and incubated it with several acetyltransferases, including PCAF, p300, CBP, and GCN5, individually (Figure 2A). Interestingly, when the GluA1ct was probed for lysine acetylation, we observed a marked increase in GluA1 acetylation in assays that contained p300 and a trend of increase with the p300 homolog CBP (Figure 2B). However, this was not observed in assays containing PCAF or GCN5. This result indicates a specific role for the p300 family of acetyltransferases on AMPAR acetylation. p300 is well known for its role in histone acetylation for the regulation of gene expression, but it is also localized in the cytoplasm (Dancy and Cole, 2015; Kwok et al., 2006; Rotte et al., 2013; Shi et al., 2009). It is therefore possible for the endogenous p300 to acetylate AMPARs in neurons. To confirm the effect of p300 on AMPAR acetylation in vivo, we incubated primary cortical neurons with either the p300 inhibitor C646 (20 μM) (Bowers et al., 2010) or the p300 acetyltransferase activator CTPB (20 μM) (Balasubramanyam et al., 2003), for 24 h, and immunoprecipitated GluA1 for acetylation assays. Indeed, inhibition of p300 by C646 caused a decrease in GluA1 acetylation, whereas activation of p300 by CTPB increased acetylation of GluA1 (Figure 2C). Because an acetylation event often antagonizes protein ubiquitination owing to competition for the same lysine residues, we examined changes in GluA1 ubiquitination. As expected, inhibition of p300 led to an increase, whereas activation of p300 by CTPB caused a decrease in the level of GluA1 ubiquitination (Figure 2C).

Figure 2.

Figure 2

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Acetyltransferase p300 Acetylates and Stabilizes AMPARs

(A) Acetylation assays from in vitro reactions with purified acetyltransferases.

(B) Quantification shows that incubation with p300, but not CBP, PCAF, or GCN5, increased GluA1 acetylation. (n = 3 experiments).

(C) Inhibition of p300 acetyltransferase activity by C646 (40 μM, 4 h) led to reduced acetylation, whereas activation by CTPB (20 μM, 4 h) led to increased acetylation.

(D) GluA1 puncta levels were assessed by immunocytochemistry following overexpression of p300 (Total GluA1, red) (scale bar, 5 μm).

(E) Quantitative analysis showed overexpression of p300 increased total GluA1 puncta intensity. (Ctrl, n = 25 cells, 2,407 puncta; p300, n = 23 cells, 2,164 puncta).

(F and G) In HEK293T cells, overexpression of p300 increases GluA1 intensity. Additionally, expression of GluA1-4KR mutant abolishes p300-induced GluA1-WT up-regulation, indicating the lysine-dependence of p300 effect (n = 3 experiments).

∗p<0.05, ∗∗∗p<0.001. Data are mean ± SEM.

p300-Mediated Acetylation Leads to AMPAR Stabilization

Acetylation has been shown to cause stabilization of membrane proteins and expansion of protein's half-life (Alaei et al., 2018; Caron et al., 2005; Drazic et al., 2016; Mak et al., 2014). To determine whether acetylation by p300 confers AMPAR with enhanced stability, we transfected p300, together with GFP, in primary hippocampal neurons. Immunostainings showed an overexpression of p300 led to an increase in the total GluA1 puncta intensity (Figures 2D and 2E). In addition, we transfected p300 with GFP-GluA1 into HEK293T cells and measured the total GluA1 levels by western blotting analysis. In line with our findings in neurons, expression of p300 led to an increase in total GluA1 levels compared with the pcDNA control, whereas expression of PCAF did not affect the amount of GluA1 (Figures 2F and 2G). These results showed that p300 acetyltransferase activity facilitates AMPAR acetylation and stabilization, supporting that p300 functions as the acetyltransferase for AMPAR acetylation.

The Lysine Residues in the GluA1 C-Terminal Tail Are the Targets for p300-Mediated AMPAR Acetylation

Because the acetyl group is conjugated to lysine residues of the substrate during acetylation, the four lysine residues located in the GluA1 C terminus are potential candidate sites for p300-mediated acetylation. To confirm the acetylation sites, we mutated all four of the lysine residues in GluA1ct to arginine (GluA1-4KR). Arginine's side group mimics the charge of lysine's side group thus preserving structural integrity but is incapable of being acetylated (Inuzuka et al., 2012). We transfected HEK293 cells with GFP-GluA1-4KR, together with p300, PCAF, or control vector pcDNA, respectively, and used the cell lysates to assess GluA1 protein levels to evaluate p300 effects on GluA1-4KR accumulation. Indeed, the previously observed increase in GluA1-WT levels from p300 overexpression was abolished in cells expressing GFP-GluA1-4KR (Figures 2F and 2G), indicating that the C-terminal lysine residues are required for p300-mediated GluA1 acetylation and stabilization.

Acetylation of GluA1 Suppresses the Aβ-Induced Reduction of AMPAR Amount and Synaptic Accumulation

Because acetylation reduces the rate of AMPAR turnover and increases AMPAR accumulation in neurons (Wang et al., 2017), we hypothesize that acetylation should lead to suppression of Aβ-induced AMPAR degradation. To test this idea, we incubated DIV 15 hippocampal neurons with Aβ alone, or with the SIRT2 inhibitor B2, for 24 h. We found that treatment with B2 (2 μM) alone resulted in an increase in both total and surface GluA1 (Figures 3A–3C). Importantly, Aβ-induced reduction in AMPARs was blocked by co-incubation with B2 (Figures 3A–3C).

Figure 3.

Figure 3

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Acetylation Stabilizes AMPAR Synaptic Localization

(A) Cultured hippocampal neurons were treated with B2, to inhibit SIRT2 (Total GluA1, green; Surface GluA1, red) (scale bar, 5 μm).

(B–C) Quantification showed B2 treatment increased GluA1 puncta localization and blocked Aβ-induced reduction in GluA1 as measured by GluA1 (B) total and (C) surface puncta intensity (Ctrl, n = 17 cells, 21,486 puncta; Aβ, n = 19 cells, 25,742 puncta; B2, n = 17 cells, 14,838 puncta; B2 + Aβ, n = 17 cells, 11,524 puncta).

(D) CTPB treatment, to activate acetyltransferase activity of p300, followed by immunocytochemistry probing of GluA1 (Total GluA1, green; Surface GluA1, red) (scale bar, 5 μm).

(E–F) Quantification showed CTPB treatment increased GluA1 puncta localization and blocked Aβ-induced reduction in GluA1 puncta intensity as measured by GluA1 (E) total and (F) surface puncta intensity. (Ctrl, n = 10 cells, 2,615 puncta; Aβ, n = 11 cells, 3,964 puncta; CTPB, n = 8 cells, 4,383 puncta; CTPB + Aβ, n = 8 cells, 3,363 puncta).

(G) Overexpression of p300 increased total GluA1 puncta intensity and blocked Aβ-induced reduction (Ctrl, n = 7 cells, 336 puncta; Aβ, n = 10 cells, 332 puncta; p300, n = 10 cells, 337 puncta; p300 + Aβ, n = 9 cells, 351 puncta).

(H) Aβ treatment of hippocampal neurons overexpressing GluA1-WT-GFP or GluA1-4KQ-GFP acetylation mimetic (Surface GluA1, red) (scale bar, 5 μm).

(I) Quantitative analysis of surface expressing exogenous GluA1 normalized to total puncta expressing exogenous GluA1 showed GluA1-4KQ-GFP increased GluA1 surface expression and blocked Aβ-induced decrease in surface GluA1 levels (GluA1-WT, n = 8 cells, 798 puncta; GluA1-WT + Aβ, n = 9 cells, 943 puncta; GluA1-4KQ, n = 9 cells, 901 puncta; GluA1-4KQ + Aβ, n = 8 cells, 862 puncta).

∗p<0.05, ∗∗p<0.01, ∗∗∗p<0.001. Data are mean ± SEM.

To examine the role of acetyltransferase activity in Aβ-induced AMPAR reductions, DIV 15 hippocampal neurons were incubated with p300 acetyltransferase activator CTPB (20 μM), together with or without Aβ, for 24 h. We found that activation of p300 by CTPB resulted in an increase in total and surface GluA1 puncta (Figures 3D–3F). Similar to the effect of Sirt2 inhibition, activation of p300 resulted in a blockade of the Aβ-induced AMPAR reduction (Figures 3D–3F). To directly test the effect of the acetyltransferase, primary neurons were transfected with p300 at DIV 8, which were then incubated with Aβ at DIV14 for 24 h. Consistently, we found that, compared with control neurons expressing GFP, which showed a reduction in GluA1 by Aβ treatment, no changes were detected on GluA1 puncta intensity in neurons overexpressing p300 (Figure 3G).

GluA1 Acetylation Mimetic Confers AMPAR Resistance to the Aβ-Induced Down-Regulation

It has been shown that substitution of lysine with glutamine mimics constitutive acetylation as glutamine's hydrophilic and uncharged structure imitates that of an acetylated lysine (Kim et al., 2006). We therefore mutated the four lysine residues of GluA1 to glutamine (GluA1-4KQ) and used the construct as a GluA1 acetylation mimetic (Wang et al., 2017). We transfected DIV 8 hippocampal neurons with GFP-GluA1-WT or GFP-GluA1-4KQ and compared their expression after 1 week. Consistent with the effect of acetylation, we found that, compared with GFP-GluA1-WT, GFP-GluA1-4KQ retained significantly higher levels of surface expression relative to the total expressed at the synapse (Figures 3H and 3I). To determine whether this acetylation mimetic was also able to block the effect of Aβ on AMPAR levels, we treated GFP-GluA1-WT or GFP-GluA1-4KQ transfected DIV 14 neurons with Aβ for 24 h. Although Aβ incubation reduced the surface expression of GFP-GluA1-WT, the expression of acetyl-mimetic GFP-GluA1-4KQ was not changed in the presence of Aβ oligomers (Figures 3H and 3I). These results demonstrate that acetylated AMPARs become resistant to Aβ-induced down-regulation.

AMPAR Acetylation Suppresses Aβ-Induced Receptor Endocytosis

Our previous work and studies of others have shown that Aβ exposure causes AMPAR ubiquitination and internalization (Guntupalli et al., 2017; Miñano-Molina et al., 2011; Zhang et al., 2018). We wondered whether the acetylation of AMPARs also plays a role in the regulation of Aβ-induced internalization. To test this idea, we incubated DIV 14 hippocampal neurons with Aβ alone, or with CTPB, for 24 h and performed internalization assays. We found that CTPB treatment (20 μM) suppressed AMPAR internalization at basal conditions, indicated by a reduction of the ratio of internalized to surface GluA1 (Figures 4A and 4B). Furthermore, although treatment with Aβ alone (1 μM) resulted in an increase in AMPAR internalization as expected, co-incubation with CTPB abolished the Aβ effect on AMPAR trafficking (Figures 4A and 4B). It was possible that CTPB affected AMPAR trafficking via off-target effects of p300 activity. To directly determine the role of AMPAR acetylation in Aβ-induced receptor internalization, we examined receptor internalization using the GluA1 acetylation mimetic. DIV 8 cultured neurons were transfected with GFP-GluA1-WT or GFP-GluA1-4KQ, which were then treated with Aβ or vehicle control for 24 h before performing internalization assays on DIV 15. We found that the basal internalization of GFP-GluA1-4KQ was reduced compared with GFP-GluA1 (Figures 4C and 4D). Importantly, although Aβ treatment enhanced the internalization of GFP-GluA1, not significant effect was observed in cells expressing GFP-GluA1-4KQ (Figures 4C and 4D). These results indicate that modulation of AMPARs by direct acetylation causes suppression of both basal and Aβ-induced AMPAR internalization.

Figure 4.

Figure 4

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Acetylation Blocks Aβ-Induced Receptor Internalization

(A) Internalization assay of hippocampal neurons treated with CTPB, to activate acetyltransferase activity of p300, or CTPB with Aβ (Surface GluA1, green; Internalized GluA1, red) (scale bar, 5 μm).

(B) Quantification of the puncta intensity of internalized GluA1 to initial surface total GluA1 (internalized + remaining surface) showed CTPB treatment blocked Aβ-induced internalization of GluA1 (Ctrl, n = 19 cells, 2,095 puncta; Aβ, n = 19 cells, 2,124 puncta; CTPB, n = 19 cells, 6,230 puncta; CTPB + Aβ, n = 19 cells, 3,341 puncta).

(C) Internalization assay of hippocampal neurons overexpressing GluA1-WT or GluA1-4KQ with or without Aβ (Internalized GluA1, red) (scale bar, 5 μm).

(D) Quantitative analysis of the puncta intensity of internalized GluA1-GFP or GluA1-4KQ-GFP to total GluA1-GFP or GluA1-4KQ-GFP expressed at that puncta. Quantification showed Aβ-induced internalization of GluA1 is suppressed by overexpression of GluA1-4KQ (GluA1-WT, n = 26 cells, 2,637 puncta; GluA1-WT + Aβ, n = 20 cells, 2,161 puncta; GluA1-4KQ, n = 20 cells, 1,897 puncta; GluA1-4KQ + Aβ, n = 20 cells, 3,018 puncta).

∗p<0.5, ∗∗p<0.01. Data are mean ± SEM.

AMPARs Show Reduced Levels in Acetylation in APP/PS1 Mice

In AD, AMPARs have a facilitated turnover rate, leading to a reduction in the total amount and synaptic accumulation of AMPARs. As we found that acetylation was able to stabilize AMPARs and rescue the effect of Aβ treatment in vitro, we wanted to know the role AMPAR acetylation plays in vivo and in AD conditions. As a widely used model of AD, the APP/PS1 mouse produces high levels of Aβ in the brain and demonstrates typical molecular and behavioral phenotypes of AD (McClean and Hölscher, 2014; Reinders et al., 2016; Reiserer et al., 2007; Sun et al., 2019; Trinchese et al., 2004). To determine whether AMPAR acetylation is altered in this AD animal model, we isolated GluA1 from hippocampal brain tissues of 11-month-old APP/PS1 mouse by immunoprecipitation and probed for acetylation and ubiquitination (Figure 5A). Indeed, consistent with our findings from rat primary neurons and human AD brains, this mouse model showed a significant reduction in the level of GluA1 acetylation, as well as an increase in GluA1 ubiquitination (Figures 5B and 5C). A reduction in GluA1 acetylation was also observed in APP/PS1 mice at 5 months old (Figure S2). The APP/PS1 mouse also showed significant reduction in the total amount of AMPARs, including GluA1 and GluA2, as well as the presynaptic proteins including synapsin I and synaptophysin, and the postsynaptic protein PSD95 (Figures 5F–5H). These changes in synaptic proteins are consistent with the known loss of synapses in the AD mouse (McClean and Hölscher, 2014; Shi et al., 2017).

Figure 5.

Figure 5

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Viral Brain Injection of GluA1-4KQ Restores GluA1 Expression and Synaptic Accumulation and Rescues the Visual Episodic Memory Deficit in APP/PS1 Mice

(A) Hippocampal tissue from 11-month-old wild-type and APP/PS1 mouse brains was homogenized and immunoprecipitated with antibody against GluA1. GluA1 acetylation and ubiquitination levels were detected through probing the immunoprecipitated GluA1 with anti-Acetyl-Lysine or ubiquitin antibodies, respectively.

(B) Quantitative analysis of the GluA1 acetylation levels showed a reduction in AMPAR acetylation in APP/PS1 mice (n = 3 experiments).

(C) Quantification analysis of the GluA1 ubiquitination levels showed an increase in AMPAR ubiquitination in APP/PS1 mice (n = 3 experiments)

(D) Timeline of the experiment. AAV was injected into the bilateral ventricles of wild-type mice or APP/PS1 mice at 11 months.

(E) AAV expression was observed (green) 6 weeks after injection. Cell nuclei were stained with Hoechst (blue) to show the cortex and hippocampus (scale bar, 500 μm).

(F) GluA1, GluA2, synapsin I, synaptophysin, and PSD95 levels were detected by western blotting in mouse hippocampus. GAPDH was used as a loading control (n = 3 per group).

(G) Quantification shows a reduction in synaptic markers in APP/PS1 mouse brains with an increase in GluA1 from AAV injection of GluA1-WT or GluA1-4KQ.

(H) GluA1, GluA2, synapsin I, and PSD95 were detected by western blotting in whole-cell lysates, cytosolic fractions, and synaptosomal fractions of mouse hippocampus.

∗p<0.05, ∗∗p<0.01, ∗∗∗p<0.001. Data are mean ± SEM.

Viral Expression of GluA1 and Its Acetylation Mimetic in APP/PS1 Mice

A reduction in AMPAR synaptic accumulation and the consequential suppression in synaptic strength is believed to be an early pathobiology in AD (Baglietto-Vargas et al., 2018; Hsieh et al., 2006; Kamenetz et al., 2003; Li et al., 2019; Lin et al., 2019; Sun et al., 2019; Ting et al., 2007). We therefore wanted to know whether stabilization of AMPARs by acetylation confers positive effects toward AD conditions. To examine the role of AMPAR acetylation for memory impairments in the AD animals, we injected AAV viruses expressing either GFP-GluA1-WT or GFP-GluA1-4KQ into the bilateral ventricles of 11-month-old APP/PS1 mice (Figure 5D). Another group of APP/PS1 mice were injected with a virus expressing only GFP as a control (APP/PS1-con). Six weeks after bilateral injection of the viruses, brain tissues were collected for examination. Brain slices revealed strong GFP signals, indicating efficient viral expression of the constructs (Figure 5E). Western blots of APP/PS1 hippocampal brain lysates showed a significant reduction in synaptic proteins including GluA1, GluA2, synapsin I, synaptophysin, and PSD95 (Figures 5F and 5G). Similar changes were observed in the cortex (Figures S1A and S1B). In APP/PS1 mice injected with either GFP-GluA1-WT or GFP-GluA1-4KQ, we found a specific increase in GluA1 in both the hippocampus (Figures 5F and 5G) and, to a lesser extent, in the cortex (Figures S1A and S1B) compared with APP/PS1 controls. Compared with GluA1-WT, GluA1-4KQ overexpression rescued GluA1 more significantly in APP/P1 mice (Figures 5H and S1C). It is noteworthy that GluA1 expression was preferentially increased in the synaptosomal fractions relative to the cytosolic fractions (Figures 5H and S1C). These results indicate the successful expression of the viral GluA1 and GluA1-4KQ AMPAR subunits at the synaptic sites of these brain regions.

Expression of GluA1 Acetylation Mimetic Rescues Deficits in Synaptic Plasticity in the APP/PS1 Mice

Synaptic plasticity serves as the molecular basis for learning and memory (Humeau and Choquet, 2019; Lüscher and Malenka, 2012; Nabavi et al., 2014; Parkinson and Hanley, 2018), which is known to be impaired in AD conditions (Colom-Cadena et al., 2020; Lambert et al., 1998; Li and Selkoe, 2020; Sánchez-Rodríguez et al., 2019; Shankar et al., 2008; Styr and Slutsky, 2018; Walsh et al., 2002). We wanted to know whether the improved synaptic expression of AMPARs by viral injection of GluA1-4KQ had any effect on synaptic function. Using hippocampal brain slices, we examined the expression of long-term potentiation (LTP) by recordings of field excitatory postsynaptic potentials (fEPSPs). Consistent with previous reports, recordings from APP/PS1 mice showed a significant reduction in LTP expression when compared with the wild-type mice (Gelman et al., 2018; Gengler et al., 2010; Da Silva et al., 2016; Trinchese et al., 2004; Vargas et al., 2014; Vyas et al., 2020) (Figures 6A and 6B). However, APP/PS1 mice expressing viral GFP-GluA1-4KQ had substantially improved LTP, whereas expression of GFP-GluA1-WT showed some rescue but to a lesser extent (Figures 6A and 6B). These results indicate that restoration of AMPAR stability and synaptic accumulation rescues synaptic plasticity.

Figure 6.

Figure 6

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Overexpression of GluA1-4KQ Rescues Hippocampal LTP and the Visual Episodic Memory Deficit in APP/PS1 Mice

(A) LTP recordings of fEPSP in acute hippocampal slices from AAV-injected wild-type mice or APP/PS1 mice.

(B) Quantitative analysis of the normalized fEPSP slope (n = 2 animals per condition, 3 brain slices per animal).

(C) The experimental design of novel object recognition test (NOR). One day before the memory acquisition, the mice were habituated to the arenas for 5 min, as indicated in the first box. The second box showed the acquisition trial. The third and fourth boxes showed the test trial conducted 1 and 24 h after the acquisition trial.

(D) The discrimination index of 1 and 24 h test trials.

(E) The recognition index between objects A and B in the acquisition trial.

(F) The recognition index between objects A and C in the test trial 1 h after the acquisition trial.

(G) The recognition index between objects A and D in the test trial 24 h after the acquisition trial (n = 5 animals).

∗p<0.05, ∗∗p<0.01, ∗∗∗p<0.001. Data are mean ± SEM.

Expression of GluA1 Acetylation Mimetic Rescues Visual Episodic Memory Deficits in APP/PS1 Mice

To examine the effect of GluA1 expression on cognitive function in the AD mice, we first performed the novel object recognition test to assess visual episodic memory in the virally injected APP/PS1 mice. Animals were first habituated to the apparatus by allowing them to explore the cage prior to the test. The animals were then allowed to familiarize themselves with the initial objects A and B. The preference index from the familiarization period showed a lack of preference for either of the objects (data not shown). After 1 and 24 h, animals were brought back to the cage with object B being replaced with object C and then object D (Figure 6C). As measured by the discrimination index, APP/PS1 mice struggled to remember the familiar object and thus failed to discriminate between the objects (Figure 6D). In the familiarization stage, none of the animals showed a particular preference of either of the objects (Figure 6E). During the 1 and 24 h tests, APP/PS1 mice spent similar amounts of time with familiar object A and either of the novel objects C or D, respectively, indicating impairments in short-term and long-term memory (Figures 6F and 6G). APP/PS1 mice expressing viral GluA1 spent significantly more time with the novel object compared with the familiar object in both the 1 and 24 h tests (Figures 6F and 6G). Viral expression of GluA1-WT led to modest improvements in memory, whereas more robust rescue effects were observed in animals expressing the acetylation mimetic GluA1-4KQ, at both 1 and 24 h after training (Figure 6D). These findings indicate that addition of acetylated, and thus stabilized, AMPARs is capable of correcting the impairments in memory capacity in AD mice.

GluA1 Acetylation Mimetic in APP/PS1 Mice Rescues Spatial Memory

We next sought to investigate the role of AMPAR acetylation in spatial learning and memory by the Morris water maze. In this test, mice were trained over a period of 4 days to learn the location of an escape platform in a pool of water using spatial cues placed within the testing room. On the second day of training, the control APP/PS1 mice had difficulties in finding the platform, whereas mice with GluA1-4KQ or GluA1 virus were able to find the platform as fast as WT mice (Figures 7A and 7B). The difference in performance was maintained for a substantial amount of time; at the end of training on day 4, mice expressing GluA1-4KQ still performed significantly better than those expressing viral GFP (Figure 7C).

Figure 7.

Figure 7

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Overexpression of GluA1-4KQ Rescues the Spatial Learning and Memory Deficit in APP/PS1 Mice

(A) The latency to reach the hidden platform during training in Morris Water Maze.

(B) The latency of day 2 of the training.

(C) The latency of day 4 of the training.

(D) The representative searching trace after removing the platform in the probe trial at 1 and 24 h after training.

(E) Left: The number of crosses over the platform site after removing the platform (1 h) during the probe trial. Right: The percentage of time spent in target quadrant.

(F) Left: The number of crosses over the platform site after removing the platform (24 h) during the probe trial. Right: The percentage of time spent in target quadrant (n = 5 animals).

∗p<0.05, ∗∗p<0.01, ∗∗∗p<0.001. Data are mean ± SEM.

At 1 and 24 h after spatial acquisition training, animals were placed back in the pool with the escape platform removed to test spatial memory (Figure 7D). Animals with intact memory can remember the location of the escape platform from training and are expected to spend time exploring the area where the platform was previously located. We analyzed the number of events when animals swam across the platform's former location, as well as the time spent in the target quadrant of the pool. In the 1 h post-training test, GluA1-4KQ expressing animals made significantly more crossings over the target location and had a significant increase in the time spent in the target quadrant, compared with APP/PS1 control animals (Figure 7E). Probing of spatial memory 24 h after training showed that GluA1-4KQ-expressing animals maintained a significant improvement in the number of crossings and time spent in the target quadrant compared with APP/PS1 mice (Figure 7F). These findings indicate that expression of GluA1-4KQ is capable of rescuing the impairments in spatial memory observed in APP/PS1 mice.

GluA1 Acetylation Mimetic in APP/PS1 Mice Rescues Fear Memory

To further examine the role of AMPAR acetylation in memory, we next performed a fear conditioning test. On day 1, mice were placed into the fear conditioning chamber and subjected to a stimulation protocol with a 2-s foot shock paired with a 20-s tone to condition a fear response. After 24 h the animals were placed back into the same box under the same environmental conditions, and the contextual memory was assessed by quantifying the amount of time spent freezing and the number of freezing instances. One hour after the contextual memory text, the entire environment of the box was changed, including both odorants and wall and floor materials/design. One hour after exposure to this new context, the cued memory was measured by quantifying the amount of freezing time and number of freezes made after the conditioned tone was played (Figure 8A).

Figure 8.

Figure 8

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Overexpression of GluA1-4KQ Rescues Fear Memory Deficits in APP/PS1 Mice

(A) The schematic diagram of the experimental design.

(B) The total number of freezes (B1) and total time spent freezing (B2) were detected in the contextual fear conditioning test.

(C) The total number of freezes (C1) and total time spent freezing (C2) were detected in the altered contextual fear conditioning test.

(D) The total number of freezes (D1) and total time spent freezing (D2) were detected in the tone-dependent freezing behavior test (n = 5 animals).

∗p<0.05, ∗∗p<0.01. Data are mean ± SEM.

In the contextual memory test, APP/PS1 mice showed a significant impairment in hippocampal-based, contextual fear memory compared with WT animals, with a decrease in both the number of freezing instances and total freezing time (Figure 8B). However, the APP/PS1 mice expressing GluA1-4KQ froze a significantly greater number of times (Figure 8B1) and for a greater length of time than the APP/PS1 mice (Figure 8B2), indicating improved memory of the testing chamber. In the test of cue memory, all of the animal groups showed a minimal freezing behavior in the testing chamber with an altered context, indicating no fear had been associated with this new environment (Figure 8C). However, when the tone was played, WT animals demonstrated strong cued fear memory, showing an elevation in freezing behavior, whereas APP/PS1 animals did not (Figure 8D). In contrast, APP/PS1 animals expressing GluA1-4KQ showed an increased number of freezes (Figure 8D1) and prolonged total freezing time (Figure 8D2), comparable with the level of WT animals. These results indicate that the impairments in both contextual and cued fear memory were rescued by the introduction of GluA1-4KQ in APP/PS1 mice.

In most behavior tests in our study, besides significant rescue effect when compared with APP/PS1 mice, GluA1-4KQ-overexpressing APP/PS1 mice showed a better performance than GluA1-WT-overexpressing APP/PS1 mice, indicating that GluA1-4KQ is more effective in preventing learning and memory impairments in AD animal model.

Discussion

One of the earliest pathological features of AD is an impairment in synaptic function partly due to a reduction in AMPA receptors at the synapse (Almeida et al., 2005; Baglietto-Vargas et al., 2018; Chang et al., 2006; Dong et al., 2015; Li et al., 2019; Marttinen et al., 2018). It has been shown that soluble Aβ oligomers promote AMPAR internalization and degradation (Guntupalli et al., 2017; Miñano-Molina et al., 2011). This is consistent with studies of our own, and those of others, which show an increase in ubiquitination of AMPARs in AD (Guntupalli et al., 2017; Rodrigues et al., 2016; Zhang et al., 2018) (as reviewed by Harris et al., 2020; Moraes et al., 2020; Zhu and Tsai, 2020). Findings from our recent work have revealed for the first time that AMPARs are also subject to acetylation, a new form of AMPAR regulation that antagonizes receptor ubiquitination due to competition for the same lysine residues (Wang et al., 2017). In this study, we further investigated the molecular mechanism involved in AMPAR acetylation and examined the role of AMPAR acetylation in cognitive deficits in AD.

We found that, in brain lysates from patients with AD, a reduction in total AMPAR amount is accompanied with a decrease in acetylation of AMPARs. The change in AMPAR acetylation was also observed in the brains of APP/PS1 AD mice. Consistently, treatment of neuronal cultures with soluble Aβ oligomers led to a significant reduction in the level of AMPAR acetylation.

In our previous work, SIRT2 was identified as the deacetylase for AMPAR deacetylation (Wang et al., 2017); however, the related acetyltransferase remained unknown. In this study, we discovered that p300 functions as the acetyltransferase responsible for AMPAR acetylation. Although p300 is generally known for its role in acetylation of nuclear histone proteins, it also localizes in the cytosol where it acetylates various substrates (Aslan et al., 2015; Dancy and Cole, 2015; Kwok et al., 2006; Rotte et al., 2013; Sebti et al., 2014; Shi et al., 2009). Our results demonstrate that p300 acetyltransferase activity triggers acetylation of AMPARs, resulting in a reduced rate in receptor internalization and degradation, leading to an increase in AMPAR cell-surface expression and elevated accumulation at the synapse.

The implication of AMPAR acetylation in brain function may vary depending on the basal levels of AMPAR protein amount and the extent of AMPAR acetylation. In this study, an increase in AMPAR acetylation led to improvements in memory in the APP/PS1 AD mice. Under AD conditions, a dramatic reduction in overall AMPAR amount is a major factor in causing synaptic weakening and impairments in cognition. Therefore, reintroduction of the acetylated and stabilized AMPARs restores the level of AMPARs and synaptic activity, leading to rescue of AD-related memory deficits. Interestingly, over-stabilization of AMPARs via enhanced receptor acetylation seems to have different effect on brain function. Indeed, wild-type mice expressing the stabilized acetylation mimetic GluA1, as well as knockout mice lacking the deacetylase SIRT2, showed impairments in synaptic plasticity and memory (Wang et al., 2017). This memory impairment likely results from excessive over-stabilization of acetylated AMPARs at synapses. In normal non-AD animals, a dramatic increase in AMPAR acetylation disrupts receptor trafficking and turnover, which is probably the cause for synaptic dysregulation and memory deficits (Wang et al., 2017).

Given their crucial role in interneuronal communication and brain function, AMPARs have been identified as a therapeutic target for several neurological disorders (Hettinger et al., 2018; Lee et al., 2016; Lynch, 2006; Paula-Lima et al., 2013; Swanson, 2009; Zhang et al., 2019). Our findings provide further support for potential strategies targeting AMPARs for the treatment of AD-related cognitive dysfunctions. Thus far, the main treatment focus has been the use of positive allosteric modulators of AMPAR known as Ampakines (Bernard et al., 2010; Black, 2005; Fernandes et al., 2018; Ward et al., 2010), a few of which have gone to clinical trial. However, although compounds showed some success in animal models (Bretin et al., 2017; Giralt et al., 2017; Lauterborn et al., 2016), they have had low clinical success (Bernard et al., 2019; Trzepacz et al., 2013; Wezenberg et al., 2007). Owing to a lack of chemical diversity among the Ampakines, alternative strategies for AMPAR-based treatment are being considered (Chang et al., 2012; Hao et al., 2015; Lee et al., 2016; Zhao et al., 2019). Our results provide a basis for pharmacological manipulation of AMPAR acetylation as a potential therapeutic strategy. On a broader level, because ubiquitination, a modulation antagonizing acetylation and resulting in receptor degradation, is enhanced in AD (Gadhave et al., 2016; Liu et al., 2019; Tramutola et al., 2018), manipulation of both of these opposing processes should be considered for more efficient management of AD.

In conclusion, our results show that the acetylation of AMPARs leads to a blockage of Aβ-induced reduction of AMPARs at the synapse by preventing receptor internalization, resulting in significant improvements in learning and memory in the transgenic AD mice. These findings encourage future efforts to identify novel compounds that enhance AMPAR acetylation as potential therapeutic tools for patients with AD.

Limitations of the Study

In APP/PS1 mice, GluA1 acetylation mimetic GluA1-4KQ was introduced by viral expression, the effect of endogenous AMPAR acetylation will be explored in future studies by overexpressing the acetyltransferase p300, or by application of its enzyme activators. Also, the findings were based on primary neurons and an AD mouse model; thus, their value for translational medicine in humans remains unclear.

Resource Availability

Lead Contact

Further information and requests for resources should be directed to and will be fulfilled by the Lead Contact, Dr. Hengye Man (hman@bu.edu; rong.liu@hust.edu.cn).

Materials Availability

This study did not generate new unique reagents.

Data and Code Availability

This study did not generate datasets or code.

Methods

All methods can be found in the accompanying Transparent Methods supplemental file.

Acknowledgments

We would like to thank the Man Lab members for helpful discussion. This work was supported by NIH grant R01 MH079407 (H.-Y.M.), National Natural Science Foundation of China (No: 31771189, R.L.; No: 31900685, Y.-P. S.), and Fundamental Research Funds for the Central Universities, HUST (No: 2019kfyXKJC079, R.L.). The authors declare no competing financial interests.

Author Contributions

This study was directed and supervised by H.-Y.M. and R.L. M.O. and Y.-P.S. performed most of the experiments and the data analysis. G.W. performed some acetylation westerns. W.-T.H. participated in animal behavior tests. W.-T.H., Z.-D.X., and X.-C.W provided some APP/PS1 AD mouse brain tissue and some reagents. M.O. and H.-Y.M. wrote the manuscript. R.L. and Y.-P.S. assisted in manuscript preparation.

Declaration of Interests

The authors declare that there is no potential conflict of interest.

Published: September 25, 2020

Footnotes

Supplemental Information can be found online at https://doi.org/10.1016/j.isci.2020.101465.

Contributor Information

Rong Liu, Email: rong.liu@hust.edu.cn.

Heng-Ye Man, Email: hman@bu.edu.

Supplemental Information

Document S1. Transparent Methods and Figures S1 and S2
mmc1.pdf (1.5MB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Document S1. Transparent Methods and Figures S1 and S2
mmc1.pdf (1.5MB, pdf)

Data Availability Statement

This study did not generate datasets or code.

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