Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs

Parcon, Paul A.; Balasubramaniam, Meenakshisundaram; Ayyadevara, Srinivas; Jones, Richard A.; Liu, Ling; Reis, Robert J. Shmookler; Barger, Steven W.; Mrak, Robert E.; Griffin, W. Sue T.

doi:10.1016/j.jalz.2017.07.754

Cited by 88 publications

(82 citation statements)

References 45 publications

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“…Our results provide evidence of the AD relevance of risk genes, but it is also important to identify the regulatory elements and transcriptional factors that regulate the expression of these genes for molecular dissection of disease etiology [45, 46]. Recent study have shown that APOEε4 genotype suppress transcription of autophagy mRNA’s by competing with transcription factor EB for binding to coordinated lysosomal expression and regulation(CLEAR) DNA motifs [47]. TFs were identified for each module with high normalized enrichment scores (NES ≥ 4) from iRegulon (Methods), which correspond to an estimated false discovery rate of less than 0.01 [33] (Supplemental Table 5).…”

Section: Resultsmentioning

confidence: 99%

Genetic perturbations of disease risk genes in mice capture transcriptomic signatures of late-onset Alzheimer’s disease

Pandey

Graham

Uyar

et al. 2019

Preprint

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BackgroundNew genetic and genomic resources have identified multiple genetic risk factors for late-onset Alzheimer’s disease (LOAD) and characterized this common dementia at the molecular level. Experimental studies in model organisms can validate these associations and elucidate the links between specific genetic factors and transcriptomic signatures. Animal models based on LOAD-associated genes can potentially connect common genetic variation with LOAD transcriptomes, thereby providing novel insights into basic biological mechanisms underlying the disease.MethodsWe performed RNA-Seq on whole brain samples from a panel of six-month-old female mice, each carrying one of the following mutations: homozygous deletions of Apoe and Clu; hemizygous deletions of Bin1 and Cd2ap; and a transgenic APOEε4. Similar data from a transgenic APP/PS1 model was included for comparison to early-onset variant effects. Weighted gene co-expression network analysis (WGCNA) was used to identify modules of correlated genes and each module was tested for differential expression by strain. We then compared mouse modules with human postmortem brain modules from the Accelerating Medicine’s Partnership for AD (AMP-AD) to determine the LOAD-related processes affected by each genetic risk factor.ResultsMouse modules were significantly enriched in multiple AD-related processes, including immune response, inflammation, lipid processing, endocytosis, and synaptic cell function. WGCNA modules were significantly associated with Apoe−/−, APOEε4, Clu−/−, and APP/PS1 mouse models. Apoe−/−, GFAP-driven APOEε4, and APP/PS1 driven modules overlapped with AMP-AD inflammation and microglial modules; Clu−/− driven modules overlapped with synaptic modules; and APP/PS1 modules separately overlapped with lipid-processing and metabolism modules.ConclusionsThis study of genetic mouse models provides a basis to dissect the role of AD risk genes in relevant AD pathologies. We determined that different genetic perturbations affect different molecular mechanisms comprising AD, and mapped specific effects to each risk gene. Our approach provides a platform for further exploration into the causes and progression of AD by assessing animal models at different ages and/or with different combinations of LOAD risk variants.

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Section: Resultsmentioning

confidence: 99%

Genetic perturbations of disease risk genes in mice capture transcriptomic signatures of late-onset Alzheimer’s disease

Pandey

Graham

Uyar

et al. 2019

Preprint

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“…Lamp2 expression is up-regulated by MCS, which is involved in fusing the lysosome to the autophagosome to facilitate autophagy (88). Lamp2 is decreased in AD apolipoprotein E4/E4 brains, potentially driving early onset AD pathology (89). Ppt1, which is up-regulated by MCS, has been linked to both endosomal dysfunction and increased apoptotic pathway activity in neuronal ceroid lipofuscinosis (90).…”

Section: Discussionmentioning

confidence: 99%

Long‐term effects of maternal choline supplementation on CA1 pyramidal neuron gene expression in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease

et al. 2019

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Choline is critical for normative function of 3 major pathways in the brain, including acetylcholine biosynthesis, being a key mediator of epigenetic regulation, and serving as the primary substrate for the phosphatidylethanolamine N‐methyltransferase pathway. Sufficient intake of dietary choline is critical for proper brain function and neurodevelopment. This is especially important for brain development during the perinatal period. Current dietary recommendations for choline intake were undertaken without critical evaluation of maternal choline levels. As such, recommended levels may be insufficient for both mother and fetus. Herein, we examined the impact of perinatal maternal choline supplementation (MCS) in a mouse model of Down syndrome and Alzheimer's disease, the Ts65Dn mouse relative to normal disomic littermates, to examine the effects on gene expression within adult offspring at ∼6 and 11 mo of age. We found MCS produces significant changes in offspring gene expression levels that supersede age‐related and genotypic gene expression changes. Alterations due to MCS impact every gene ontology category queried, including GABAergic neurotransmission, the endosomal‐lysosomal pathway and autophagy, and neurotrophins, highlighting the importance of proper choline intake during the perinatal period, especially when the fetus is known to have a neurodevelopmental disorder such as trisomy.—Alldred, M. J., Chao, H. M., Lee, S. H., Beilin, J., Powers, B. E., Petkova, E., Strupp, B. J., Ginsberg, S. D. Long‐term effects of maternal choline supplementation on CA1 pyramidal neuron gene expression in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease. FASEB J. 33, 9871–9884 (2019). http://www.fasebj.org

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“…A third, independent connection between Alzheimer pathology and TFEB function was reported with the observation that TFEB binding to the promoters of lysosomal genes can be outcompeted by apolipoprotein E4 (apoE4) (Parcon et al . ). ApoE4 is the protein encoded by the APOE ɛ4 allele, the single greatest genetic risk factor for the development of Alzheimer's disease (Strittmatter and Roses ).…”

Section: Impaired Tfeb Signaling In Neurodegenerative Diseasementioning

confidence: 97%

“…In vitro, apoE4 could bind to DNA probes carrying the CLEAR motif with much greater affinity than apoE3, the protein product of APOE ɛ3 allele which is not a risk factor for Alzheimer's disease; increased apoE4 binding to CLEAR probes was paralleled by decreased TFEB binding to the same probes, and expression of apoE4 diminished the expression of TFEB target genes (Parcon et al . ). Thus, several independent pathways seem to converge to disturbed TFEB‐mediated lysosomal biogenesis as a potential common leitmotif in the pathogenesis of Alzheimer's disease.…”

Section: Impaired Tfeb Signaling In Neurodegenerative Diseasementioning

confidence: 97%

Lysosome biogenesis in health and disease

Bajaj

Lotfi

Pal

et al. 2018

Journal of Neurochemistry

119

116

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This review focuses on the pathways that regulate lysosome biogenesis and that are implicated in numerous degenerative storage diseases, including lysosomal storage disorders and late-onset neurodegenerative diseases. Lysosomal proteins are synthesized in the endoplasmic reticulum and trafficked to the endolysosomal system through the secretory route. Several receptors have been characterized that execute post-Golgi trafficking of lysosomal proteins. Some of them recognize their cargo proteins based on specific amino acid signatures, others based on a particular glycan modification that is exclusively found on lysosomal proteins. Nearly all receptors serving lysosome biogenesis are under the transcriptional control of transcription factor EB (TFEB), a master regulator of the lysosomal system. TFEB coordinates the expression of lysosomal hydrolases, lysosomal membrane proteins, and autophagy proteins in response to pathways sensing lysosomal stress and the nutritional conditions of the cell among other stimuli. TFEB is primed for activation in lysosomal storage disorders but surprisingly its function is impaired in some late-onset neurodegenerative storage diseases like Alzheimer's and Parkinson's, because of specific detrimental interactions that limit TFEB expression or activation. Thus, disrupted TFEB function presumably plays a role in the pathogenesis of these diseases. Multiple studies in animal models of degenerative storage diseases have shown that exogenous expression of TFEB and pharmacological activation of endogenous TFEB attenuate disease phenotypes. These results highlight TFEB-mediated enhancement of lysosomal biogenesis and function as a candidate strategy to counteract the progression of these diseases. This article is part of the Special Issue "Lysosomal Storage Disorders".

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Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs

Abstract: ApoE4-CLEAR interactions may account for suppressed autophagy in APOE ɛ4/ɛ4 carriers and, in this way, contribute to earlier AD onset.

Cited by 88 publications

References 45 publications

Genetic perturbations of disease risk genes in mice capture transcriptomic signatures of late-onset Alzheimer’s disease

Genetic perturbations of disease risk genes in mice capture transcriptomic signatures of late-onset Alzheimer’s disease

Long‐term effects of maternal choline supplementation on CA1 pyramidal neuron gene expression in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease

Lysosome biogenesis in health and disease

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