Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer’s disease-like pathology

Nuriel, Tal; Angulo, Sergio; Khan, Usman; Ashok, Archana; Chen, Qiuying; Figueroa, Helen Y.; Emrani, Sheina; Liu, Li; Herman, Mathieu; Barrett, Geoffrey M.; Savage, Valerie; Buitrago, Luna; Cepeda-Prado, Efraín; Fung, Christine; Goldberg, Eliana; Gross, Steven S.; Hussaini, S. Abid; Moreno, Herman; Small, Scott A.; Duff, Karen

doi:10.1038/s41467-017-01444-0

Cited by 149 publications

(164 citation statements)

References 84 publications

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“…As the endosomal-lysosomal dysregulation that we observed in the brains of aged APOE4 mice was not restricted to the EC 30 , this may play a role in the APOE4-associated bioenergetic deficits that we observed in the Hip and Ctx of these mice. On the other hand, the neuronal hyperactivity that we observed appears to be primarily localized to the EC within the hippocampal formation 33 . Intriguingly, neuronal activity and glucose utilization have previously been shown to exist in a near 1:1 stoichiometric relationship 72 , suggesting that the bioenergetic counterbalancing that we observe in the EC of aged APOE4 mice may be directly correlated to the observed neuronal hyperactivity in these mice 33 .…”

Section: Discussionmentioning

confidence: 51%

“…Taken together, our data suggest that, in contrast to other brain region such as the hippocampus and cortex, the EC of aged APOE4 mice exhibits an increased rate of oxidative metabolism and ATP turnover, as compared to aged APOE3 mice. We hypothesize that this differential regional mitochondrial respiration that we observe here is downstream of the decreased glucose utilization observed in APOE4 carriers [16][17][18] and may be related to the neuronal hyperactivity that we observed in the EC of aged APOE4 mice 33 . In addition, we hypothesize that the unique bioenergetic compensatory mechanisms that we observe in the EC may lead to an increased rate of Table 3.…”

Section: Metabolitementioning

confidence: 55%

“…In order to investigate the source of these differential bioenergetic effects in the EC, we conducted a series of additional analyses on the EC of aged male APOE4/4 vs APOE3/3 mice. We have already published on an untargeted metabolomics study that we performed on metabolites extracted from the EC and PVC of 14-15 month-old male APOE4/4 vs. APOE3/3 mice, which is part of a larger study elucidating the effects APOE4 expression on neuronal hyperactivity 33 . Intriguingly, this metabolomics study uncovered increases in numerous energy-related metabolites, including several TCA cycle metabolites (malate, citrate and isocitrate), as well as fructose-6-phosphate, carnitine, and ATP, each of which had higher levels in the EC of the aged APOE4/4 vs. APOE3/3 mice (Fig.…”

Section: Computational Analysis Of Untargeted Metabolomics Data Reveamentioning

confidence: 99%

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APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice

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Pera

et al. 2020

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the ε4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimer's disease (AD). However, the reason for the association between APOE4 and AD remains unclear. While much of the research has focused on the ability of the apoE4 protein to increase the aggregation and decrease the clearance of Aβ, there is also an abundance of data showing that APOE4 negatively impacts many additional processes in the brain, including bioenergetics. In order to gain a more comprehensive understanding of APOE4′s role in AD pathogenesis, we performed a transcriptomics analysis of APOE4 vs. APOE3 expression in the entorhinal cortex (EC) and primary visual cortex (PVC) of aged APOE mice. This study revealed EC-specific upregulation of genes related to oxidative phosphorylation (OxPhos). Follow-up analysis utilizing the Seahorse platform showed decreased mitochondrial respiration with age in the hippocampus and cortex of APOE4 vs. APOE3 mice, but not in the EC of these mice. Additional studies, as well as the original transcriptomics data, suggest that multiple bioenergetic pathways are differentially regulated by APOE4 expression in the EC of aged APOE mice in order to increase the mitochondrial coupling efficiency in this region. Given the importance of the EC as one of the first regions to be affected by AD pathology in humans, the observation that the EC is susceptible to differential bioenergetic regulation in response to a metabolic stressor such as APOE4 may point to a causative factor in the pathogenesis of AD. Possession of the ε4 allele of apolipoprotein E (APOE) is the major genetic risk factor for late-onset Alzheimer's disease (AD). In normal physiology, the apoE protein plays a vital role in the transport of cholesterol and other lipids through the bloodstream, as well as within the brain 1-3. Although the three common isoforms of apoE (E2, E3 and E4) differ from each other at only two amino acids-apoE2 (Cys112, Cys158), apoE3 (Cys112, Arg158), apoE4 (Arg112, Arg158)-this small change in amino acid sequence has a large effect on the protein structure, resulting in differential affinities towards apoE's lipid cargo, as well as its receptors [see reviews by 1,4 ].

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Section: Discussionmentioning

confidence: 51%

Section: Metabolitementioning

confidence: 55%

Section: Computational Analysis Of Untargeted Metabolomics Data Reveamentioning

confidence: 99%

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APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice

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“…These results demonstrated that blocking neuron surface glycans with AAL and WGA induced the hyperexcitability of hippocampal neurons. It has been reported that neuronal hyperactivity is an early phenotype in Alzheimer’s disease and could trigger apoptosis of neurons(Abiega et al , 2016; Nuriel et al , 2017). Our results demonstrated that declined glycosylation on the cell surface of hippocampal neurons can induce hyperexcitability and further apoptosis, which implied the important role of glycosylation in the pathogenesis of the Alzheimer’s disease.…”

Section: Resultsmentioning

confidence: 99%

Multilayered N-glycoproteomics reveals impaired N-glycosylation promoting Alzheimer’s disease

Pan

Xie

Sang

et al. 2019

Preprint

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25Alzheimer's disease (AD) is one of the most common neurodegenerative diseases that 26 currently lacks clear pathogenesis and effective treatment. Protein glycosylation is 27 ubiquitous in brain tissue and site-specific analysis of N-glycoproteome, which is 28 technically challenging, can advance our understanding of the glycoproteins' role in 29 AD. In this study, we profiled the multilayered variations in proteins, N-glycosites, 30 N-glycans, and in particular site-specific N-glycopeptides in the APP/PS1 and wild 31 type mouse brain through combining pGlyco 2.0 strategy with other quantitative 32 N-glycoproteomic strategies. The comprehensive brain N-glycoproteome landscape 33 was constructed, and rich details of the heterogeneous site-specific protein 34 N-glycosylations were exhibited. Quantitative analyses explored generally 35 downregulated N-glycosylation involving proteins such as glutamate receptors, as 36 well as fucosylated and oligo-mannose type glycans in APP/PS1 mice versus wild 37 type mice. Moreover, our preliminary functional study revealed that N-glycosylation 38 was crucial for the membrane localization of NCAM1 and for maintaining the 39 excitability and viability of neuron cells. Our work offered a panoramic view of the 40 N-glycoproteomes in Alzheimer's disease and revealed that generally impaired 41 N-glycosylation promotes Alzheimer's disease progression. 42Keywords: Quantitative N-glycoproteomics, Alzheimer's disease, Glutamate receptor, 43 N-glycan, Neuron hyperexcitability 44 4 7 glycan patterns was constructed ( Fig. 1B). Of the identified proteins, 276 were 103 exclusively contributed by the N-glycoproteome data (Fig. 1C). Among the total 104 1,493 N-glycosites, 423 and 689 N-glycosites were only identified by "N-glycosites" 105 and "site-specific N-glycopeptides" strategies, respectively, while 381 glycosites were 106 co-identified by the two strategies (Fig. 1D). The multi-omic data provided a 107 panoramic view of the proteomes, N-glycoproteomes and glycomes in the APP/PS1 108 mouse and wild type mouse brain. 109 Complex and heterogeneous N-glycoproteome landscape of the110 APP/PS1 mouse and wild type mouse brain 111 The micro-heterogeneity of protein N-glycosylation was exhibited through analyzing 112 the distribution of glycosites and site-specific glycopeptides on the glycoproteins. 113About 58.4% of N-glycoproteins have one N-glycosite, while the 7.6% most severely 114 N-glycosylated proteins have more than 5 sites ( Fig. 2A). The average number of 115 N-glycosites per glycoprotein is 2. The distribution of N-glycoforms on each site was 116 shown in Fig. 2B. The average number of glycoforms per site is 3.3, while there are 117 35 N-glycosites had more than 14 N-glycans on each of them. Proteins having the 118 most glycosites and the most heterogeneous sites were listed in the Figure (Fig. 2A 119 and B). Combining both information, the most heterogeneous glycoproteins in mouse 120 brain were listed in Figure EV1A. AT1B2, THY1, EAA2, and NPTN exhibited the 121 severest micro-...

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“…Therefore, ApoE4 is a specific and severe NMDA receptor functional suppressor at the postsynaptic membrane. Accordingly, undue amplification of weak excitatory signals has been reported for ApoE4 knock-in mice (Nuriel et al, 2017). This compensatory phenotype is likely related to the substantially elevated Aβ levels shared by ApoE4 knock-in mice (Liraz et al, 2013), ApoE4/APPind mice (Bales et al, 2009) and human ApoE4 carriers (Monsell et al, 2015).…”

Section: Apoe Polymorphisms Are Predominant Risk Factors For Spomentioning

confidence: 98%

The pathological hallmarks of Alzheimer’s disease derive from compensatory responses to NMDA receptor insufficiency

Sohre

Moosmann

2018

Preprint

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Alzheimer's disease is characterized by intracellular aggregates of hyperphosphorylated tau protein and extracellular plaques of amyloid β peptide, a product of APP processing. The origin of these pathological hallmarks has remained elusive. Here, we have tested the idea that both alterations, at the onset of the disease, may constitute compensatory responses to the same causative and initial trigger, namely NMDA receptor insufficiency. Treatment of rat cortical neurons with the specific NMDA receptor antagonist AP5 within 4 h caused a significant increase in tau phosphorylation at the AT8 and S404 epitopes as well as an increase in APP expression and Aβ40 secretion. Single intraperitoneal injections of the NMDA receptor open channel blocker MK-801 into wild-type mice reproduced all of these changes in a brain region-specific fashion either at latency 4 h or 24 h. Subchronic treatment with MK-801 for 6 weeks induced AT8, S404 and S396 immunoreactivity selectively in female mice. We conclude that the pivotal pathological alterations in Alzheimer's disease represent runaway physiological responses to persistently insufficient excitatory neurotransmission. In view of the evidence for excitatory insufficiency in trisomy 21 patients, PS1 mutation carriers and ApoE4 carriers, our data suggest a common pathomechanism behind familial, sporadic, and risk allele-triggered Alzheimer's disease. The potential of this mechanism to reconcile previous conflicting observations is discussed.

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Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer’s disease-like pathology

Cited by 149 publications

References 84 publications

APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice

APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice

Multilayered N-glycoproteomics reveals impaired N-glycosylation promoting Alzheimer’s disease

The pathological hallmarks of Alzheimer’s disease derive from compensatory responses to NMDA receptor insufficiency

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