Secreted by Neurons, ApoE4 Makes Tangles and Degeneration Worse

Compared to their glial neighbors, neurons make a small amount of apolipoprotein E. Yet when it comes in the form of ApoE4, the protein punches above its weight in the tauopathy-addled brain, according to a study published February 20 in Nature Aging. Researchers led by Yadong Huang at the University of California, San Francisco, reported that, in mice expressing human ApoE4, deleting it specifically from neurons not only drastically reduced the accumulation of hyperphosphorylated tau and the progression of tangle pathology across the brain, but also prevented gliosis, myelin loss, and neurodegeneration. Nixing ApoE4 from neurons also stopped neurons, oligodendrocytes, astrocytes, and microglia from transitioning into disease-associated transcriptional states. In all, the findings cast neuronal ApoE4 as an instigator in the tau cascade, driving both pathology and its consequences to the brain.

  • In tauopathy model, culling ApoE4 from neurons drastically reduced tangles.
  • Neuronal ApoE4 exacerbated neurodegeneration, astrogliosis, microgliosis, myelin loss.
  • Removing ApoE4 from neurons stanched disease-linked states in neurons, glia.

“This work provides further evidence for ApoE4’s role in influencing a multitude of events that drive AD progression beyond simply influencing amyloid accumulation, and importantly, this work contributes novel insights regarding cell-type-specific effects of ApoE4,” commented Elizabeth Mormino of Stanford University.

As the strongest genetic risk factor for late-onset Alzheimer’s disease, ApoE4 has been implicated in multiple aspects of AD pathogenesis, including amyloid accumulation, lipid metabolism, neuroinflammation and, more recently, tau pathophysiology. In a revealing example of the relationship between ApoE and tau, a rare, protective variant in ApoE fended off tau, but not Aβ pathology, in a carrier of an autosomal-dominant AD mutation (Nov 2019 news; Sep 2022 news). In the tau-P301S, aka PS19 mouse model of tauopathy, human ApoE4 dramatically worsened tau accumulation, gliosis, and neurodegeneration (Sep 2017 news). While wiping out microglia assuaged this, astrocytes were also to blame, and removing ApoE4 from them curbed tau-mediated neurodegeneration (Oct 2019 news; Apr 2021 news).

Huang has for years built the case that neuronal ApoE is important in AD pathogenesis (Xu et al., 2006; Jun 2018 news; May 2021 news). In the current work, first author Nicole Koutsodendris and colleagues zeroed in on what neuronal ApoE4 does in the PS19 model. They started with mice expressing floxed human ApoE3 or ApoE4 genes in place of the mouse gene, used neuron-expressed Cre recombinase to remove these floxed genes, and crossed these lines to PS19. They confirmed that the ApoE deletion occurred only in neurons, resulting in 20-25 percent less total ApoE protein in the hippocampus.

With this fleet of transgenics, the researchers first asked if neuronal ApoE3 or ApoE4 removal would nudge tau accumulation. They found a surprisingly large effect. The brains of 10-month-old PS19-E4 mice were overrun with hyperphosphorylated tau and neurofibrillary tangles, but taking ApoE4 out of neurons reduced hyperphosphorylated tau by 81 percent and halved neurofibrillary tangles. PS19-E3 mice had substantially less tau pathology than did E4s, and removal of ApoE3 from their neurons had no effect. For comparison, a previous study reported that removing ApoE4 from astrocytes lessened tau accumulation by 30-40 percent in PS19 mice of a similar age (Wang et al., 2021).

Stoking Tau. Hyperphosphorylated tau (brown) is abundant in PS19-E4 mice (top left). Removing ApoE4 from neurons lessens tau accumulation by 81 percent (bottom left). PS19-E3 mice have less tau (top right), and though removing neuronal ApoE3 reduces this further, the effect was not significant (bottom right). Percent tangle coverage in ApoE4 (red), ApoE4 neuronal knockout (pink), ApoE3 (blue), and ApoE3 KO (green) brain is shown on far right. [Courtesy of Koutsodendris et al., Nature Aging, 2023.]

Neuronal ApoE4 also pushed tau propagation across the brain. The researchers injected 10-month-old ApoE4 transgenics with an adeno-associated virus expressing P301S tau. Three months later, hyperphosphorylated tau had robustly increased near the injection site and in anatomically connected regions on the contralateral side of the brain. Deleting ApoE4 from neurons cut this propagation by half, down to the level seen in E3 mice. The findings suggest that when ApoE4 comes from neurons, it aids and abets spread of misfolded tau.

“The current results provide the exciting perspective that ApoE4 may enhance the spread of tau pathology from the medial temporal lobe to other connected brain areas, which needs to be tested in future studies in patients with AD,” commented Michael Ewers of Ludwig Maximilian University in Munich. Ewers' previous work tied ApoE4 genotype to accelerated spatiotemporal progression of tau pathology, as measured by tau-PET (Neitzel et al., 2020). 

Missing Myelin. PS19-E4 mice lost myelin (green) in the stratum radiatum of the hippocampus (top left) relative to PS19-E3 mice (top right). Nixing neuronal ApoE4 prevented this loss (bottom left), whereas knocking out ApoE3 did little (bottom right). [Courtesy of Koutsodendris et al., Nature Aging, 2023.]

Giving neuronal ApoE4 the boot shielded against neurodegeneration. The hippocampi of PS19-E4 mice were about 25 percent smaller than those in PS19-E3 mice—a decrement that was corrected when neurons were relieved of the ApoE4 gene. The same was true for other measures of neurodegeneration, including enlarged ventricles, thinning of the hippocampal CA1 layer, and the number of neurons expressing markers of cell death. Similarly, removal of neuronal ApoE4 stemmed the loss of oligodendrocytes, oligodendrocyte progenitor cells, and myelin.

Other glial cells were profoundly affected by ApoE4, as well. The scientists detected rampant microgliosis and astrogliosis in PS19-E4, but not PS19-E3 mice. Eliminating neuronal ApoE4 prevented both forms of gliosis. More than any other outcome measured in the study, the area covered by CD68-positive microglia in PS19-E4 mice correlated best with hippocampal shrinkage. To the authors, this cast microglial activation as the strongest contributor to neuronal ApoE4-promoted hippocampal degeneration in tauopathy.

Did neuronal ApoE4 influence gene expression? In single-nuclei transcriptomics analyses, subclusters of neurons, oligodendrocytes, astrocytes, and microglia were more abundant when neurons expressed ApoE4. These subclusters shared some transcriptional signatures, including upregulation of a suite of heat shock proteins as well as ubiquitin, suggesting they were in a state of distress. In astrocytes and microglia, ApoE4 was among the upregulated genes.

Aggravated Microglia. CD68+ microglia (green) abound in the hippocampi of PS19-E4 mice (top left) relative to PS19-E3 mice (top right). Removal of neuronal ApoE4 quells this (bottom left). [Courtesy of Koutsodendris et al., Nature Aging, 2023.]

How to interpret these findings given that astrocytes or even microglia are primary sources of ApoE4? To Huang, the data amount to a working model. He believes that when tau starts accumulating in neurons, ApoE4 produced by those neurons exacerbates tau accumulation and spread, and skews neuronal changes in response to tau accumulation, such as by stoking expression of major histocompatibility complex I, which could potentially activate lymphocytes, as this group reported previously (Zalocusky et al., 2021). As such, he believes neuronal ApoE4 initiates the first phase of a toxic cascade. In the second phase, neuronal distress signals compel glia to respond and multiply. In the third phase, these glial responses start to do more harm than good, leading to synaptic damage, myelin loss, and neurodegeneration. Huang thinks that ApoE4 produced by astrocytes and microglia likely play a role in the last two phases. The findings suggest that specific removal of ApoE4 from neurons could shut down this vicious cycle, Huang told Alzforum.

To Huang’s UCSF colleague Lennart Mucke, who was not involved in the study, the findings support Huang’s long-held hypothesis that ApoE expression by stressed neurons promotes the development of AD. “This pathomechanism offers diverse opportunities for novel therapeutic interventions,” he wrote to Alzforum.

Mormino thinks the work brings us closer to understanding the drivers of AD pathology. “For instance, the finding that neuronal ApoE4 influences tau propagation via connected neurons offers a specific mechanism for a key transitional state in the AD cascade,” she wrote. “It also highlights that the mechanisms driving key AD phenotypes, such as the spread of pathological tau, may differ as a function of ApoE genotype.”

The minimal tau accumulation in the tauopathy mice devoid of neuronal ApoE4 aligns with tau-PET observations in humans, where ApoE4 inheritance was linked to more extensive tau accumulation, noted Joseph Therriault and Pedro Rosa-Neto in a comment to Alzforum. Considered together, the mouse and human data suggest that ApoE4 from neurons accelerates tau pathology among E4 carriers.—Jessica Shugart

Comments

  1. This impressive work details a series of experiments highlighting a central role of neuronal APOE4 in multiple AD phenotypes that are critical for disease progression, including tau accumulation, neurodegeneration, neuronal hyperexcitability, and myelin deficits.

    This work provides further evidence for APOE4’s role in influencing a multitude of events that drive AD progression beyond simply influencing amyloid accumulation. Importantly, this work contributes novel insights regarding cell-type specific effects of APOE4.

    These findings have significant implications for AD treatment strategies. Given that lowering APOE4 levels is a potential therapeutic strategy for AD, treatments that specifically target neuronal APOE4 may be effective in preventing dementia and at the same time avoid negative side effects that have been associated with lowering APOE4 levels in a non-specific fashion. 

    This work also contributes to the conceptualization of AD more broadly. Although the events underlying AD (tau accumulation and spread, neurodegeneration, etc.) have been characterized in many animal models and in human biomarker studies, this work brings us closer to understanding the mechanistic drivers of the AD cascade. 

    For instance, the finding that neuronal APOE4 influences tau propagation via connected neurons offers a specific mechanism for a key transitional state in the AD cascade, given the close correspondence between tau spread and clinical signs of dementia in humans. It also highlights that the mechanisms driving key AD phenotypes such as tau spread may differ as a function of APOE genotype. If neuronal APOE4 drives tau propagation, it is possible that other mechanisms may drive propagation in APOE3/3 individuals with widespread tau. This potential heterogeneity along the APOE-tau axis highlights that there may be individual differences in how a given individual progresses along the AD cascade, as opposed to a one-size-fits all model of disease progression. If this is true, it may be the case that APOE-genotype-specific treatments will be necessary for effective AD therapeutics, whether these treatments manipulate APOE directly or indirectly via mechanisms influenced by APOE.

    View all comments by Elizabeth Mormino

  2. It is well established that the APOE ε4 allele is associated with higher amyloid plaque levels in Alzheimer’s disease. APOE ε4 may contribute to tau pathology in cortical brain areas mostly via increased levels of amyloid plaques, yet APOE ε4-related increases of tau-PET predominantly in the medial temporal lobe have been reported (Therriault et al., 2020), suggesting that APOE may modulate more directly the formation of tau pathology in AD.

    However, the mechanisms that may link APOE to tau pathology are not well understood. Addressing this research question, Koutsodendris and colleagues generated floxed APOE KI mice crossed with the PS19-tau mouse model in order to express homozygous human APOE ε4 or ε3 alleles across all major cell types. The authors report that the APOE ε4 mice showed higher levels of AT8- and thioflavine-detected tau compared to the APOE ε3 mice, consistent with previous results on human APOE ε4 in P301S mice (Shi et al., 2017). 

    These effects were dramatically reduced in those APOE ε4 mice in which APOE ε4 expression was lowered selectively in neurons through neuron-specific CRE recombinase expression (APOE ε4-Cre mice), suggesting that APOE ε4 expression in neurons was pivotal to increased tau pathology.

    Furthermore, seeding tau via injection of AAV2-P301S-mutant tau into the hippocampus showed increased p-tau levels in the contralateral non-injected hippocampus in the APOE ε4 compared to APOE ε3 and APOE ε4-Cre mice, suggesting the APOE ε4 enhances the propagation of tau pathology between brain regions.

    These results inform previous studies showing a transsynaptic and axonal propagation of fibrillar tau in vitro and in vivo (Clavaguera et al., 2009; de Calignon et al., 2012). The propagation of tau cannot be studied in humans. Even so, we and others have previously found that higher functional and structural connectivity to brain regions of early high tau-PET accumulation, such as the medial temporal lobe, is predictive of higher tau accumulation in the connected brain regions in patients with AD (Franzmeier et al., 2020; Franzmeier et al., 2020; Vogel et al., 2021). 

    The current results provide the exciting perspective that APOE ε4 may enhance the spreading of tau pathology from the medial temporal lobe to other connected brain areas, which needs to be tested in future studies in patients with AD.

    The study by Koutsodendris et al. suggests several hypothesis-generating mechanisms that may underlie the link between APOE ε4 and increased tau pathology. The APOE ε4 mice showed a decrease in the levels of myelin and oligodendrocyte coverage in the hippocampus, the presence of neuronal hyperexcitability, and increased levels of microgliosis and astrogliosis when compared to the APOE-ε4-Cre mice. Sn-RNA transcriptomics of hippocampal tissue revealed several clusters of altered gene expression in oligodendrocytes, microglia, and neurons.

    The study did not assess which of these brain alterations may be essential for APOE ε4 to increase tau pathology, or whether those brain alterations occur downstream of tau pathology. However, it is tempting to speculate on their role in the APOE-dependent increase in tau pathology. Previous studies support that APOE ε4 is associated with reduced myelin levels in the brain (Blanchard et al., 2022), and demyelination may precede overt tau pathology in transgenic mice (Desai et al., 2009), suggesting that myelin alterations may play a role in the etiology of tau. We and others previously provided evidence suggesting that those brain regions connected by ontogenetically less-myelinated fiber tracts are more susceptible to tau pathology in AD (Rubinski et al., 2022; Braak et al., 2018). Given that myelin is impaired in AD (Moscoso et al., 2022; Zhan et al., 2014), which is associated with higher biomarker levels of phospho-tau (Dean et al., 2017), it will be important to assess whether APOE ε4 is associated with altered myelin levels and thus higher tau accumulation in patients with AD.

    Furthermore, in the current study, APOE ε4 was associated with altered microglial gene expression. Previous studies showed that APOE expression is greatly increased in microglia activated in mouse models of amyloid pathology (Krasemann et al., 2017). Given that amyloid plaque deposition triggers dramatic changes in microglia gene signatures including TREM2, it will be important to assess in the future whether APOE ε4 alters the amyloid-related microglia signature and thus tau pathology downstream of amyloid pathology.

    Lastly, synaptic transmission of tau occurs in an activity-dependent manner (Wu et al., 2016). Previous findings in mouse models of amyloidosis suggest an increased in hyperexcitability (Busche and Hyman, 2020). It remains to be tested whether APOE ε4 induces neuronal hyperexcitability and thus higher tau transmission.   

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    Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, Jucker M, Goedert M, Tolnay M. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009 Jul;11(7):909-13. PubMed.

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    Rubinski A, Franzmeier N, Dewenter A, Luan Y, Smith R, Strandberg O, Ossenkoppele R, Dichgans M, Hansson O, Ewers M, Alzheimer’s Disease Neuroimaging Initiative (ADNI). Higher levels of myelin are associated with higher resistance against tau pathology in Alzheimer's disease. Alzheimers Res Ther. 2022 Sep 24;14(1):139. PubMed.

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    Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, Beckers L, O'Loughlin E, Xu Y, Fanek Z, Greco DJ, Smith ST, Tweet G, Humulock Z, Zrzavy T, Conde-Sanroman P, Gacias M, Weng Z, Chen H, Tjon E, Mazaheri F, Hartmann K, Madi A, Ulrich JD, Glatzel M, Worthmann A, Heeren J, Budnik B, Lemere C, Ikezu T, Heppner FL, Litvak V, Holtzman DM, Lassmann H, Weiner HL, Ochando J, Haass C, Butovsky O. The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity. 2017 Sep 19;47(3):566-581.e9. PubMed.

    Wu JW, Hussaini SA, Bastille IM, Rodriguez GA, Mrejeru A, Rilett K, Sanders DW, Cook C, Fu H, Boonen RA, Herman M, Nahmani E, Emrani S, Figueroa YH, Diamond MI, Clelland CL, Wray S, Duff KE. Neuronal activity enhances tau propagation and tau pathology in vivo. Nat Neurosci. 2016 Aug;19(8):1085-92. Epub 2016 Jun 20 PubMed.

    Busche MA, Hyman BT. Synergy between amyloid-β and tau in Alzheimer's disease. Nat Neurosci. 2020 Oct;23(10):1183-1193. Epub 2020 Aug 10 PubMed.

    View all comments by Michael Ewers

  3. Koutsodendris and colleagues characterize the effects of neuronal APOE4 on AD pathologies in a mouse model of tauopathy. When removing neuronal human APOE4, the authors observed a striking, approximately 50 percent, reduction in hippocampal tau pathology, assessed using thioflavine S staining for tau neurofibrillary tangles. These findings align with previous observations conducted in humans by many research groups, including ours (Therriault et al., 2020; Baek et al., 2020; La Joie et al., 2021; Young et al., 2023).

    The authors also studied APOE4-associated tau propagation by injecting a virus encoding human mutant tau into the hippocampi of fE mice with and without Syn1-Cre and assessing tau load to the non-injected side 12 weeks later. They observed, using AT8 immunostaining, that fE4 mice had substantial p-tau propagation to the contralateral hippocampus, a finding not observed in the fE4/Syn1-Cre or fE4 mice. Interestingly, this supports APOE4’s impact on tau pathology through mechanisms such as increasing promotion of both aggregation and spread.

    The authors also showed that APOE4 removal suppresses neurodegeneration signatures observed in neurons, oligodendrocytes, astrocytes, and microglia from elderly PS19-fE4/3 mice, also complementing work in humans by the late George Bartzokis (2007). Koutsodendris' findings highlight the importance of APOE4-associated glial responses in AD.

    This research supports the use of emerging biomarkers to assess the harmful effects of APOE4 in neuronal and glial compartments. We look forward to the next steps regarding possible interventions targeting such APOE4-associated vulnerabilities, particularly in the presence of Aβ pathology.

    References:

    Therriault J, Benedet AL, Pascoal TA, Mathotaarachchi S, Chamoun M, Savard M, Thomas E, Kang MS, Lussier F, Tissot C, Parsons M, Qureshi MN, Vitali P, Massarweh G, Soucy JP, Rej S, Saha-Chaudhuri P, Gauthier S, Rosa-Neto P. Association of Apolipoprotein E ε4 With Medial Temporal Tau Independent of Amyloid-β. JAMA Neurol. 2020 Apr 1;77(4):470-479. PubMed.

    Baek MS, Cho H, Lee HS, Lee JH, Ryu YH, Lyoo CH. Effect of APOE ε4 genotype on amyloid-β and tau accumulation in Alzheimer's disease. Alzheimers Res Ther. 2020 Oct 31;12(1):140. PubMed.

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    Young CB, Johns E, Kennedy G, Belloy ME, Insel PS, Greicius MD, Sperling RA, Johnson KA, Poston KL, Mormino EC, Alzheimer’s Disease Neuroimaging Initiative, A4 Study Team. APOE effects on regional tau in preclinical Alzheimer's disease. Mol Neurodegener. 2023 Jan 4;18(1):1. PubMed.

    Bartzokis G, Lu PH, Geschwind DH, Tingus K, Huang D, Mendez MF, Edwards N, Mintz J. Apolipoprotein E affects both myelin breakdown and cognition: implications for age-related trajectories of decline into dementia. Biol Psychiatry. 2007 Dec 15;62(12):1380-7. PubMed.

    View all comments by Joseph Therriault View all comments by Pedro Rosa-Neto
    • User Profile Image Yang Shi
      Chinese Institute for Brain Research
    • Posted:

    We previously reported that ApoE has a significant impact on tau pathogenesis and tau-associated neurodegeneration. ApoE4 increases tau pathology and neurodegeneration relative to ApoE3 and ApoE2, whereas global apoE deficiency is strongly protective (Shi et al, 2017). Accumulating evidence suggests that the cellular source of ApoE matters. ApoE is mainly produced by glia cells in the brain, and not much in neurons under physiological conditions, although in certain stressful conditions, neurons can express ApoE. Recently, astrocytic ApoE4, but not ApoE3, was found to promote tau pathology and tau-associated neurodegeneration (Wang et al., 2021). 

    The current study shows that neuronal ApoE4 is instrumental in inducing tau pathogenesis and neurodegeneration. Deletion of neuronal ApoE4 drastically reduces tau pathology by 81, a much stronger effect than from astrocytic apoE4 deletion, although the level of neurodegeneration rescue is similar. However, the lack of non-tau Tg control mice in this study makes it difficult to assess how far away the rescue is from the normal state. Deletion of neuronal ApoE3 had no effect on tau pathology or neurodegeneration, which is likely due, in part, to the already less pathology in ApoE3 tau mice.

    The marked effect of neuronal ApoE on tau pathology and neurodegeneration is surprising, because neuronal ApoE expression is low even in neurodegenerative conditions. This is supported by no significant change in total brain ApoE level in TE4 or TE3 mice upon neuronal ApoE deletion.

    The key question is, how does neuronal apoE4 mechanistically drive disease progression? We previously found that microglia serve as the fundamental driving force of both tau pathogenesis and neurodegeneration (Shi et al., 2019). When microglia are depleted for three months during the critical time window of disease onset, both tau pathology and neurodegeneration are fully rescued. Interestingly, depleting microglia using the CSF1R inhibitor PLX3397 dramatically increased ApoE4 level in TE4 mouse brain. The increased ApoE4 mainly comes from astrocytes, but a portion is notably present in neurons (which may be due to increased neuronal ApoE4 expression or increased ApoE4 uptake). However, despite this exceptionally high level of ApoE4 in neurons and in the brain environment, no atrophy occurs in the absence of microglia. Therefore, if neuronal ApoE does something, microglia may act downstream of it to drive disease progression. It would be interesting to overexpress neuronal ApoE4 in tauopathy mice while depleting microglia to dissect out the role of microglia in mediating neuronal ApoE4s effects.

    What, then, is the connection between neuronal ApoE4 and microglia? There are multiple possibilities. For instance, neuronal ApoE4 may cell-autonomously cause injury to neurons, and injured neurons can generate factors that activate microglia. In this case, ApoE4 may interact with tau to promote tau pathogenesis that further induces neuronal damage, or ApoE4 may directly cause neuronal injury through certain mechanisms. The same group reported that neuronal ApoE4, but not neuronal ApoE3, nor astrocytic ApoE4, is subject to fragmentation that confers cellular toxicity, which is associated with higher p-tau levels (Brecht et al., 2004). They also reported that neuronal ApoE4 increases neuronal MHC-I expression, which is linked to p-tau formation (Zalocusky et al., 2021). Certainly, there can be other cellular mechanisms through which ApoE4 impacts neuronal functions.

    Another possibility is that ApoE4 particles derived from neurons may have special traits that make them more effective in activating microglia. Since neuronal ApoE only constitutes a small pool of brain ApoE, it will have to be highly effective in activating microglia.

    A third possibility is that neuronal ApoE4 may mediate the crosstalk between neurons and other brain cell types, thus enabling it to impact other brain cell functions that subsequently induce microglial activation. This is indicated by the reduction of oligodendrocytic ApoE4 expression upon neuronal ApoE4 deletion. It is possible that oligodendrocytes act downstream of neuronal ApoE4-induced effects to trigger microglial activation.

    In general, the phenotype shown in this paper is striking and interesting. One point worth noting is that, typically, ApoE4 level is lower than ApoE3 in the peripheral blood and the brain in APOE KI mice as well as in humans, while the current study shows even higher brain ApoE4 level than ApoE3. Whether this represents a physiological state is not clear.

    The finding provides important insights if the data can be replicated by future studies. ApoE from various brain cell types likely all play a role in regulating tau pathogenesis and neurodegeneration through direct or indirect regulation of microglial activation.

    References:

    Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, Tsai RM, Spina S, Grinberg LT, Rojas JC, Gallardo G, Wang K, Roh J, Robinson G, Finn MB, Jiang H, Sullivan PM, Baufeld C, Wood MW, Sutphen C, McCue L, Xiong C, Del-Aguila JL, Morris JC, Cruchaga C, Alzheimer’s Disease Neuroimaging Initiative, Fagan AM, Miller BL, Boxer AL, Seeley WW, Butovsky O, Barres BA, Paul SM, Holtzman DM. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017 Sep 28;549(7673):523-527. Epub 2017 Sep 20 PubMed.

    Wang C, Xiong M, Gratuze M, Bao X, Shi Y, Andhey PS, Manis M, Schroeder C, Yin Z, Madore C, Butovsky O, Artyomov M, Ulrich JD, Holtzman DM. Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia. Neuron. 2021 May 19;109(10):1657-1674.e7. Epub 2021 Apr 7 PubMed.

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    Zalocusky KA, Najm R, Taubes AL, Hao Y, Yoon SY, Koutsodendris N, Nelson MR, Rao A, Bennett DA, Bant J, Amornkul DJ, Xu Q, An A, Cisne-Thomson O, Huang Y. Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer's disease. Nat Neurosci. 2021 Jun;24(6):786-798. Epub 2021 May 6 PubMed.

    View all comments by Yang Shi
    • User Profile Image Steve Barger
      University of Arkansas for Medical Sciences
    • Posted:

    "Secreted by Neurons ..." Excuse me, but that title is misleading. Huang and colleagues did not address secretion, receptors, or any other evidence for extracellular ApoE.

    I feel obliged to remind the readership that ApoE has a very well-documented intracellular role, binding specific cis elements that control expression of at least one relevant pathway: lysosomal autophagy. ApoE4 binds the CLEAR ("coordinated lysosomal expression and regulation) element with much greater affinity than does ApoE3, acting as a competitive inhibitor of the microphthalmia/transcription factor E (MiT/TFE) family of transcription factors, which are critical for induction of autophagy and other lysosomal functions.

    References:

    Theendakara V, Peters-Libeu CA, Spilman P, Poksay KS, Bredesen DE, Rao RV. Direct Transcriptional Effects of Apolipoprotein E. J Neurosci. 2016 Jan 20;36(3):685-700. PubMed.

    Parcon PA, Balasubramaniam M, Ayyadevara S, Jones RA, Liu L, Shmookler Reis RJ, Barger SW, Mrak RE, Griffin WS. Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs. Alzheimers Dement. 2018 Feb;14(2):230-242. Epub 2017 Sep 22 PubMed.

    Lima D, Hacke AC, Inaba J, Pessôa CA, Kerman K. Electrochemical detection of specific interactions between apolipoprotein E isoforms and DNA sequences related to Alzheimer's disease. Bioelectrochemistry. 2020 Jun;133:107447. Epub 2019 Dec 23 PubMed.

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References

Mutations Citations

  1. APOE C130R (ApoE4)

News Citations

  1. Can an ApoE Mutation Halt Alzheimer’s Disease?
  2. In Brain With Christchurch Mutation, More ApoE3 Means Fewer Tangles
  3. ApoE4 Makes All Things Tau Worse, From Beginning to End
  4. In Tauopathy, ApoE Destroys Neurons Via Microglia
  5. Squelching ApoE in Astrocytes of Tau-Ravaged Mice Dampens Degeneration
  6. In Human Neurons, ApoE4 Promotes Aβ Production and Tau Phosphorylation
  7. Does ApoE in Neurons Drive Selective Vulnerability in Alzheimer’s?

Research Models Citations

  1. Tau P301S (Line PS19)

Paper Citations

  1. Xu Q, Bernardo A, Walker D, Kanegawa T, Mahley RW, Huang Y. Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus. J Neurosci. 2006 May 10;26(19):4985-94. PubMed.
  2. Wang C, Xiong M, Gratuze M, Bao X, Shi Y, Andhey PS, Manis M, Schroeder C, Yin Z, Madore C, Butovsky O, Artyomov M, Ulrich JD, Holtzman DM. Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia. Neuron. 2021 May 19;109(10):1657-1674.e7. Epub 2021 Apr 7 PubMed.
  3. Neitzel J, Franzmeier N, Rubinski A, Pichet Binette A, Poirier J, Villeneuve S, Ewers M, PREVENT-AD Research Group and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). ApoE4 associated with higher tau accumulation independent of amyloid burden. Alzheimer's & Dementia, 07 December 2020 Alzheimer's & Dementia
  4. Zalocusky KA, Najm R, Taubes AL, Hao Y, Yoon SY, Koutsodendris N, Nelson MR, Rao A, Bennett DA, Bant J, Amornkul DJ, Xu Q, An A, Cisne-Thomson O, Huang Y. Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer's disease. Nat Neurosci. 2021 Jun;24(6):786-798. Epub 2021 May 6 PubMed.

Further Reading

No Available Further Reading

Primary Papers

  1. Koutsodendris N, Blumenfeld J, Agrawal A, Traglia M, Grone B, Zilberter M, Yip O, Rao A, Nelson MR, Hao Y, Thomas R, Yoon SY, Arriola P, Huang Y. Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits. Nat Aging 2023 Nature Aging

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