Astrocyte Receptor Suppresses Neurotoxic Lipids, Preserves Neurons

Once overlooked, astrocytes are increasingly recognized as star players in Alzheimer’s disease, with recent studies blaming them for feeding into a neurotoxic stew that kills neurons. In the September 7 Nature Metabolism, researchers led by Haibo Zhou and Zhengzheng Xu at the Chinese Academy of Sciences in Shanghai identified the astrocyte receptor TMEM164 as a suppressor of this toxin-spewing reactive state.

  • In six different neurodegenerative diseases, reactive astrocytes suppress TMEM164.
  • This astrocyte receptor maintains homeostasis, preventing release of toxic lipids.
  • Overexpressing TMEM164 preserved neurons in mouse models of AD and PD.

Overexpressing TMEM164 kept astrocytes homeostatic even when exposed to stressors, preventing the release of toxic lipids. In mouse models of Alzheimer’s and Parkinson’s disease, boosting TMEM164 expression via an adenovirus preserved neurons, as well as memory or motor function, respectively. The findings suggest that enhancing TMEM164 could be a therapeutic strategy, the authors concluded.

Sagar Gaikwad at the University of Texas Medical Branch in Galveston agreed. “The study provides the first evidence of the regulatory role of TMEM164 in astrocyte activation within the nervous system,” he wrote to Alzforum (comment below).

Infamous Intersection. Comparing reactive astrocyte RNA-Seq datasets from Alzheimer’s, multiple sclerosis, Huntington’s, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and Parkinson’s brain revealed a single gene that is downregulated in all six: TMEM164 (center). [Courtesy of Zhang et al., Nature Metabolism.]

Previous research by Shane Liddelow at New York University and others has found that inflamed microglia release factors that prod astrocytes into a reactive state, triggering them to kill neurons in animal models of AD and PD (Jan 2017 news; Jun 2018 news). A compound that blocks this incitement, NLY01, is being tested in Parkinson's disease and diabetes, though it reported a negative Phase 2 result last spring (company press release). Later research reported the toxic factor secreted by astrocytes to be long-chain saturated fatty acids produced by the enzyme ELOVL1 (Oct 2021 news).

Zhou and colleagues sought to identify the genes that regulate astrocyte reactivity. Joint first authors Liansheng Zhang, Zhiheng Jia, and Qiang Wu exposed mouse primary astrocytes to the microglial instigators IL-1α, TNF, and C1q for six hours to trigger them, then blocked their reactivity with basic fibroblast growth factor for six hours, and finally reactivated the cells with the microglial cocktail. At each stage, the authors analyzed bulk RNA-Seq data to find genes that changed expression.

They compared these data to seven published datasets of single-nuclei RNA-Seq data from AD brain (May 2019 news; Nov 2019 news; Jan 2020 news; Jul 2021 news; Yang et al., 2022; Zhou et al., 2022; Otero-Garcia et al., 2022).

These experiments identified 10 increased and 28 decreased genes that were consistently changed in reactive astrocytes. To zero in on key players, the authors compared the set to astrocyte snRNA-Seq data from five other neurodegenerative diseases—Parkinson’s, Huntington’s, multiple sclerosis, amyotrophic lateral sclerosis, and frontotemporal lobar degeneration (May 2022 news; Jul 2020 news; Garcia et al., 2022; Jäkel et al., 2019; Pineda et al., 2021). Only a single gene changed in common in all datasets, being consistently repressed in reactive astrocytes: TMEM164.

Suppressed Toxicity. When cultured mouse neurons (green) are exposed to conditioned media from reactive astrocytes (center), many die (red). Media from astrocytes overexpressing TMEM164 (right) is less toxic, similar to media from homeostatic astrocytes (left). [Courtesy of Zhang et al., Nature Metabolism.]

Scientists know little about TMEM164, a seven-membrane-pass receptor on astroglia. The authors tested its function by overexpressing it in cultured mouse astrocytes and inducing reactivity via the microglial cocktail. TMEM164+ astrocytes resisted entering a reactive state. They kept homeostatic features, such as being able to stimulate synaptogenesis and engulf synaptosomes. They expressed half as much ELOVL1 as did control astrocytes exposed to the same cocktail, and secreted fewer long-chain fatty acids. In keeping with this, media from TMEM164+ astrocytes exposed to the microglial cocktail killed few neurons (see image above).

How does TMEM164 keep the cells from reacting? Comparing RNA-Seq of TMEM164+ and control astrocytes identified numerous transcription factors repressed in the former. The authors overexpressed each one in TMEM164+ astrocytes, then applied the microglial cocktail. Only CAPN15 counteracted the inhibitory effects of TMEM164, allowing astrocytes to enter a reactive state. This suggested that CAPN15 is the downstream factor responsible for the reactive response. Indeed, turning down CAPN15 expression with CRISPR also lowered ELOVL1.

Would boosting TMEM164 alleviate neurodegeneration? The authors tested this in both the 5XFAD amyloidosis model, and an inflammation-based Parkinson’s model. For the former, they injected an adenoviral vector behind the eyes of 3-month-old mice. The vector carried TMEM164 under the control of an astrocyte promoter, and transfected 80 percent of astrocytes in the cortex. Three months later, transfected mice had fewer reactive astrocytes, more neurons, and better memory than control 5XFAD mice. At 9 months of age, they had fewer plaques.

To approximate PD, the authors injected the vector into the substantia nigra of 3-month-old wild-type mice. Three weeks later they added LPS to inflame microglia, trigger astrocyte reactivity, and kill dopaminergic neurons. TMEM164 transfection preserved neurons and movement abilities at nearly wild-type levels.

Does this occur in human cells? To test this, the authors transfected cultured human astrocytes with TMEM164 before exposing them to the microglial cocktail. As in mouse cultures, transfected cells remained homeostatic and released no toxic lipids.

In future work, the authors will investigate whether TMEM164 protects neurons in animal models of HD, MS, and ALS. If so, a universal strategy for treating neurodegenerative diseases might be developed, Zhou told Alzforum. They also plan to test the viral vectors in nonhuman primates, as a precursor to human trials.—Madolyn Bowman Rogers

Comments

  1. It’s exciting to see advancements in research that could lead to innovative clinical interventions. This study provides the first evidence of a regulatory role of TMEM164 in astrocyte activation within the nervous system. The study reported that TMEM164 overexpression inhibits the induction of neurotoxic reactive astrocytes and neuronal death in both mouse and human astrocytes, as well as in Alzheimer's and Parkinson's disease mouse models.

    The development of an adeno-associated virus (AAV)-mediated strategy for astrocyte-specific overexpression of TMEM164 offers a novel therapeutic target and approach for treating neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. The AAV-mediated strategy efficiently and specifically inhibits the activation of neurotoxic reactive astrocytes in specific brain regions or even throughout the whole brain.

    Further research by other researchers is needed to validate these findings. It's also important to fully elucidate the mechanism by which TMEM164 suppresses the release of toxic lipids and its potential as a therapeutic target for neurodegenerative diseases associated with neurotoxic reactive astrocytes.

    View all comments by Sagar Gaikwad
    • User Profile Image Julia TCW
      Boston University School of Medicine
    • Posted:

    Zhang et al. identified one target, human astrocyte-specific protein, TMEM164, which is suppressed in major neurodegenerative diseases including AD, PD, HD, MS, ALS, and FTLD patient brains through unbiased screening of overlapping molecules among these neurodegenerative diseases. This transmembrane protein was revealed as a key regulator in preventing the induction of neurotoxic reactive astrocytes. Overexpression of TMEM164 in neurotoxic brain environment showed decreased glia activation and neuronal death but increased astrocyte phagocytosis and memory function.

    Mechanistically, TMEM164 overexpression reduces the neurotoxic saturated lipid synthesis enzyme ELOVL1, potentially through downstream transcription factor CAPN15, resulting in decreased saturated lipids and reduced cell death. While further mechanisms of TMEM164 regulation should be assessed, this study indicates that saturated lipid accumulation discovered in neurodegenerative disease brains, especially AD, could be one of the main causal factors for neuronal death.

    Interestingly, six months after delivering astrocyte-targeted, BBB-penetrating AAV-Tmem164 to the mouse AD brain in vivo, astrocyte reactivity was blocked and they showed increased phagocytic, lysosomal, and autophagic profiles. This suggests that Tmem164 may be a key upstream regulator that could maintain the cellular functions of homeostatic and potential astrocyte-targeted therapeutics for common neurodegenerative disease.

    While this one target covers six different neurodegenerative diseases, this type of approach can be applied to different neurodegenerative diseases independently in subgroups of patients with different disease status. This would allow us to identify more targets to efficiently prevent neurodegeneration in a particular disease and to understand cell type-specific mechanistic interconnections of targets with disease progression.

    View all comments by Julia TCW

  3. This paper by Zhang and colleagues represents a remarkable piece of research that identifies a novel regulator of neurotoxic reactive astrocytes, which are implicated in various neurodegenerative disorders. Here, the authors have discovered that transmembrane protein TMEM164, which is normally expressed in astrocytes, is suppressed by inflammatory cytokines released from activated microglia. TMEM164 acts as a lipid sensor that maintains lipid homeostasis in astrocytes and prevents the accumulation and secretion of saturated lipids that are toxic to neurons. By overexpressing TMEM164 specifically in astrocytes, the authors were able to inhibit the induction of neurotoxic reactive astrocytes and neuronal death. Bravo! These discoveries also provide mechanistic insights into how TMEM164 regulates lipid metabolism and signaling pathways in astrocytes. We had previously discovered microglia-released cytokines that drove neurotoxic reactive astrocyte formation but had not uncovered how astrocyte autonomous factors might be contributing to the transition from physiologically “normal” astrocytes to a pathological reactive subtype.

    This paper is significant for several reasons. First, it reveals a previously unknown function of TMEM164 in astrocytes and its role in modulating astrocyte reactivity. Second, it demonstrates that TMEM164 overexpression can effectively protect neurons from neurotoxic reactive astrocytes (by inhibiting both their induction and production of toxic lipids), suggesting a potential therapeutic strategy for neurodegenerative diseases. Third, it sheds light on the molecular mechanisms of astrocyte-neuron interactions and how they are affected by inflammation and lipid dysregulation.

    The work of Zhang and colleagues also raises some interesting questions for future research, such as, how is TMEM164 expression regulated by inflammatory signals? Does TMEM164 have other functions in astrocytes or other cell types? And, are other lipid sensors or regulators involved in astrocyte reactivity?

    Overall, this paper is an incredibly valuable contribution to the field of glial biology and neurodegeneration. It provides novel insights into the regulation and function of TMEM164 in astrocytes and its impact on neuronal survival. It also offers a promising avenue for developing new interventions to prevent or treat neurodegenerative disorders by targeting astrocyte-specific TMEM164 expression.

    View all comments by Shane Liddelow

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References

News Citations

  1. Microglia Give Astrocytes License to Kill
  2. Does Taming Killer Astrocytes Spare Neurons in Parkinson’s Disease?
  3. ELOVL Hurts—Enzyme Makes Lipids That Turn Astrocytes Toxic
  4. When It Comes to Alzheimer’s Disease, Do Human Microglia Even Give a DAM?
  5. Single-Cell Expression Atlas Charts Changes in Alzheimer’s Entorhinal Cortex
  6. Human and Mouse Microglia React Differently to Amyloid
  7. Single-Cell Transcription Cum Chromatin Analysis Pins SREBF1 to AD
  8. Single-Cell Sleuthing Nabs Neurons Prone to Perish in Parkinson’s
  9. Cell-Type-Specific RNA Analysis Probes Selective Vulnerability in Huntington’s

Paper Citations

  1. Yang AC, Vest RT, Kern F, Lee DP, Agam M, Maat CA, Losada PM, Chen MB, Schaum N, Khoury N, Toland A, Calcuttawala K, Shin H, Pálovics R, Shin A, Wang EY, Luo J, Gate D, Schulz-Schaeffer WJ, Chu P, Siegenthaler JA, McNerney MW, Keller A, Wyss-Coray T. A human brain vascular atlas reveals diverse mediators of Alzheimer's risk. Nature. 2022 Mar;603(7903):885-892. Epub 2022 Feb 14 PubMed.
  2. Zhou Y, Su Y, Li S, Kennedy BC, Zhang DY, Bond AM, Sun Y, Jacob F, Lu L, Hu P, Viaene AN, Helbig I, Kessler SK, Lucas T, Salinas RD, Gu X, Chen HI, Wu H, Kleinman JE, Hyde TM, Nauen DW, Weinberger DR, Ming GL, Song H. Molecular landscapes of human hippocampal immature neurons across lifespan. Nature. 2022 Jul;607(7919):527-533. Epub 2022 Jul 6 PubMed.
  3. Otero-Garcia M, Mahajani SU, Wakhloo D, Tang W, Xue YQ, Morabito S, Pan J, Oberhauser J, Madira AE, Shakouri T, Deng Y, Allison T, He Z, Lowry WE, Kawaguchi R, Swarup V, Cobos I. Molecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer's disease. Neuron. 2022 Sep 21;110(18):2929-2948.e8. Epub 2022 Jul 25 PubMed.
  4. Garcia FJ, Sun N, Lee H, Godlewski B, Mathys H, Galani K, Zhou B, Jiang X, Ng AP, Mantero J, Tsai LH, Bennett DA, Sahin M, Kellis M, Heiman M. Single-cell dissection of the human brain vasculature. Nature. 2022 Mar;603(7903):893-899. Epub 2022 Feb 14 PubMed.
  5. Jäkel S, Agirre E, Mendanha Falcão A, van Bruggen D, Lee KW, Knuesel I, Malhotra D, Ffrench-Constant C, Williams A, Castelo-Branco G. Altered human oligodendrocyte heterogeneity in multiple sclerosis. Nature. 2019 Feb;566(7745):543-547. Epub 2019 Jan 23 PubMed.
  6. Pineda SS, Lee H, Fitzwalter BE, Mohammadi S, Pregent LJ, Gardashli ME, Mantero J, Engelberg-Cook E, DeJesus-Hernandez M, vanBlitterswijk M, Pottier C, Rademakers R, Oskarsson B, Shah JS, Petersen RC, Graff-Radford NR, Boeve BF, Knopman DS, Josephs KA, DeTure M, Murray ME, Dickson DW, Heiman M, Belzil VV, Kellis M. Single-cell profiling of the human primary motor cortex in ALS and FTLD. 2021 Jul 10 10.1101/2021.07.07.451374 (version 2) bioRxiv.

External Citations

  1. company press release

Further Reading

Primary Papers

  1. Zhang L, Jia Z, Wu Q, Bai T, Wang B, Hu X, Li T, Liu X, Fu J, Chen Y, Ding X, Liu Z, Xu Z, Zhou H. Alleviating symptoms of neurodegenerative disorders by astrocyte-specific overexpression of TMEM164 in mice. Nat Metab. 2023 Oct;5(10):1787-1802. Epub 2023 Sep 7 PubMed.

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