APOE ε4 genotype, amyloid-β, and sex interact to predict tau in regions of high APOE mRNA expression

Dincer, Aylin; Chen, Charles D.; McKay, Nicole S.; Koenig, Lauren N.; McCullough, Austin; Flores, Shaney; Keefe, Sarah; Schultz, Stephanie A.; Feldman, Rebecca L.; Joseph‐Mathurin, Nelly; Hornbeck, Russ C.; Cruchaga, Carlos; Schindler, Suzanne E.; Holtzman, David M.; Morris, John C.; Benzinger, Tammie L.S.; Gordon, Brian A.

doi:10.1126/scitranslmed.abl7646

Cited by 17 publications

(16 citation statements)

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“…We observe a significant difference between ApoE3 male and female mice, where female ApoE3 mice have 50% fewer surface-localized NMPs than male ApoE3 mice in hippocampus (Fig 2B). We find this noteworthy in the context of the extensive literature on the influence of biological sex on AD pathogenesis 24,[34][35][36][37] . We find coordinate changes in Lrp1, but fail to detect any change in a membrane-loading control such as the transferrin receptor (TFR) which should be unaffected by ApoE.…”

Section: Apoe Isoforms Differentially Modulate Nmp Surface Localizati...mentioning

confidence: 66%

“…We generated postnatal primary cortical neurons from either 20S-FLAG transgenic animals or primary embryonic cortical neurons from WT animals and conducted imaging and biochemical experiments to measure NMP localization. ApoE is a lipoprotein, and in the brain is largely thought to be released by glia in the lipid-bound form 24, 38 . Therefore, for our experiments in primary neurons we tested whether or not the lipidation of ApoE would also influence NMP localization.…”

Section: Resultsmentioning

confidence: 99%

“…Finally, using ApoE-KI/hTau-KI crosses, we find that ApoE isoforms differentially shift the aggregation threshold for Tau. Overall, our data define NMPs as a pivotal proteostasis mechanism underlying the formation of endogenous Tau aggregates, which is directly regulated by the largest genetic risk factor for late-onset Alzheimer's Disease.While the precise mechanisms underlying Tau aggregation are still debated, one major genetic factor that influences Tau aggregation and deposition is ApoE [24][25][26] . The most significant risk factor for late-onset Alzheimer's Disease is the ApoE4 isoform of the ApoE gene, while the ApoE3 isoform is neutral and the ApoE2 isoform is protective 27,28 .…”

mentioning

confidence: 99%

“…While the precise mechanisms underlying Tau aggregation are still debated, one major genetic factor that influences Tau aggregation and deposition is ApoE [24][25][26] . The most significant risk factor for late-onset Alzheimer's Disease is the ApoE4 isoform of the ApoE gene, while the ApoE3 isoform is neutral and the ApoE2 isoform is protective 27,28 .…”

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confidence: 99%

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Dysregulation of neuroproteasomes by ApoE isoforms drives endogenous Tau aggregation

Paradise

Sabu

Bafia

et al. 2022

Preprint

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Neuronal membrane proteasomes (NMPs) are a functionally transmembrane subset of 20S proteasomes that degrade newly synthesized proteins. To date, the molecular composition of NMPs is undefined, and moreover, whether NMPs can influence any aspect of protein aggregation with relevance to neurodegenerative disorders remains unexplored. Using a Cre-dependent conditional knock-in mouse line to endogenously tag the proteasome, we find that NMPs co-purify with ApoE. We discover that NMP membrane localization is differentially modulated by ApoE isoforms (E4<E3<E2)in vitro,in vivo, and in human postmortem samples. This isoform-dependent change in NMP localization inversely correlates with the risk that ApoE isoforms pose for Alzheimer’s Disease. ApoE4-dependent reduction of NMP localization is strongest in brain regions selectively vulnerable to neurodegeneration. We synthesized selective NMP-specific inhibitors and discovered that NMP inhibition induces aggregation of endogenous and newly synthesized mouse and human Tau isoforms, without the need for seeding or pathogenic mutations. We posit that newly synthesized Tau is exceptionally susceptible to aggregation due to NMP dysfunction. Stereotactic injection of NMP inhibitorsin vivoinduces aggregation, phosphorylation, somatodendritic mislocalization and pathology of endogenous newly synthesized Tau. Finally, using ApoE-KI/hTau-KI crosses, we find that ApoE isoforms differentially shift the aggregation threshold for Tau. Overall, our data define NMPs as a pivotal proteostasis mechanism underlying the formation of endogenous Tau aggregates, which is directly regulated by the largest genetic risk factor for late-onset Alzheimer’s Disease.

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Section: Apoe Isoforms Differentially Modulate Nmp Surface Localizati...mentioning

confidence: 66%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Dysregulation of neuroproteasomes by ApoE isoforms drives endogenous Tau aggregation

Paradise

Sabu

Bafia

et al. 2022

Preprint

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“…It has already been shown in mice models of AD that gene expression patterns can inform spreading of τ P [31] and human modelling of Parkinson’s disease has shown how gene expression patterns can inform regional vulnerability to create a model of toxic protein spread in Parkinson’s disease [46]. There are several candidate genes for modelling regional vulnerability in AD, most notably microtubule association protein tau (MAPT), as a proxy for relative baseline τ P vulnerability [47] and apolipoprotein-E (APOE) for those patients with the APOE ϵ 4 mutation [29, 48, 49]. While there are many other candidate genes that may influence regional vulnerability, care should be taken to avoid creating overdetermined models.…”

Section: Discussionmentioning

confidence: 99%

Personalised Regional Modelling Predicts Tau Progression in the Human Brain

Chaggar,

Vogel,

Pichet Binette

et al. 2023

Preprint

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Aggregation of the hyperphosphorylated tau protein is a central driver of Alzheimer’s disease, and its accumulation exhibits a rich spatio-temporal pattern that unfolds during the course of the disease, sequentially progressing through the brain across axonal connections. It is unclear how this spatio-temporal process is orchestrated – namely, to what extent the spread of pathologic tau is governed by transport between brain regions, local production or both. To address this, we develop a mechanistic model from tau PET data to describe tau dynamics along the Alzheimer’s disease timeline. Our analysis reveals longitudinal changes in production and transport dynamics on two independent cohorts, with subjects in early stage of the disease exhibiting transport-dominated spread, consistent with an initial spread of pathologic tau seeds, and subjects in late stage disease (Braak stage 3/4 onwards) characterised primarily by local production of tau. Furthermore, we demonstrate that the model can accurately predict subject-specific longitudinal tau accumulation at a regional level, potentially providing a new clinical tool to monitor and classify patient disease progression.TeaserA mechanistic model reveals tau protein dynamics in Alzheimer’s, showing stage-specific shifts in transport and local production.

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Combined Connectomics, MAPT Gene Expression, and Amyloid Deposition to Explain Regional Tau Deposition in Alzheimer Disease

Zheng,

Rubinski,

Denecke

et al. 2023

Annals of Neurology

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ObjectiveWe aimed to test whether region‐specific factors, including spatial expression patterns of the tau‐encoding gene MAPT and regional levels of amyloid‐PET, enhance connectivity‐based modeling of the spatial variability in tau‐PET deposition in the Alzheimer's disease (AD) spectrum.MethodsWe included 685 participants (395 amyloid‐positive participants within AD spectrum and 290 amyloid‐negative controls) with tau‐PET and amyloid‐PET from three studies (ADNI, 18F‐AV‐1451‐A05, and BioFINDER‐1). Resting‐state fMRI was obtained in healthy controls (N=1000) from the Human Connectome Project, and MAPT gene expression from the Allen Human Brain Atlas. Based on a brain‐parcellation atlas superimposed onto all modalities, we obtained ROI‐to‐ROI functional connectivity, ROI‐level PET values, and MAPT gene expression. In stepwise regression analyses, we tested connectivity, MAPT gene expression, and amyloid‐PET as predictors of group‐averaged and individual tau‐PET ROI values in amyloid‐positive participants.ResultsConnectivity alone explained 21.8–39.2% (range across three studies) of the variance in tau‐PET ROI values averaged across amyloid‐positive participants. Stepwise addition of MAPT gene expression and amyloid‐PET increased the proportion of explained variance to 30.2–46.0% and 45.0–49.9%, respectively. Similarly, for the prediction of patient‐level tau‐PET ROI values, combining all three predictors significantly improved the variability explained (mean adjusted R2 range across studies=0.118–0.148, 0.156–0.196, 0.251–0.333 for connectivity alone, connectivity plus MAPT expression, and all three modalities combined, respectively).InterpretationAcross three study samples, combining the functional connectome and molecular properties substantially enhanced the explanatory power compared to single modalities, providing a valuable tool to explain regional susceptibility to tau deposition in AD.This article is protected by copyright. All rights reserved.

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APOE ε4 genotype, amyloid-β, and sex interact to predict tau in regions of high APOE mRNA expression

Cited by 17 publications

References 83 publications

Dysregulation of neuroproteasomes by ApoE isoforms drives endogenous Tau aggregation

Dysregulation of neuroproteasomes by ApoE isoforms drives endogenous Tau aggregation

Personalised Regional Modelling Predicts Tau Progression in the Human Brain

Combined Connectomics, MAPT Gene Expression, and Amyloid Deposition to Explain Regional Tau Deposition in Alzheimer Disease

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