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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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Stanford University School of Medicine
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 MorminoLudwig Maximilian University
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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View all comments by Michael EwersMcGill University
McGill University
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 Pedro Rosa-NetoChinese Institute for Brain Research
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.
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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 ShiUniversity of Arkansas for Medical Sciences
"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.
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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.
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