Li Y, Munoz-Mayorga D, Nie Y, Kang N, Tao Y, Lagerwall J, Pernaci C, Curtin G, Coufal NG, Mertens J, Shi L, Chen X. Microglial lipid droplet accumulation in tauopathy brain is regulated by neuronal AMPK. Cell Metab. 2024 Jun 4;36(6):1351-1370.e8. Epub 2024 Apr 23 PubMed.
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National Institutes of Health
National Institutes of Health
The work from Li et al. beautifully demonstrates how upregulated lipid synthesis and downregulated lipid turnover leads to pathological lipid accumulation in both neurons and glia in multiple tauopathy model systems—iPSC-derived cells as well as transgenic flies and mice. This work uses an inventive combination of label-free imaging and metabolic labelling assays to clearly establish its findings in multiple model systems. This study contributes to the growing body of work cementing lipid accumulation as a central pathology of AD and related dementias.
In addition to adding more support to the idea that lipid accumulation is a signature of proinflammatory microglia (Haney et al., 2024; Victor et al., 2022; Prakash et al., 2023; Stephenson et al., 2024), this work adds a new mechanistic understanding of the origins of glial lipid accumulation—that it arises from unsaturated fatty acid transfer from neurons. A few questions that arise from this are: 1) What is it about the tauopathy models that leads to the increased lipid droplets in the first place? 2) Why do lipid droplets accumulate in human neurons (iPSC-derived) and not (visibly) in neurons within the tauopathy mouse models? 3) Why is there regional specificity to LD accumulation, and why do microglia near neurons with hyperphosphorylated tau accumulate LDs more than other microglia? And finally: 4) How could we bolster the capacity of microglia and astrocytes to handle these lipids?
Li et al. demonstrate that increasing lipid turnover through AMPK signaling alleviates lipid accumulation in neurons and its non-cell-autonomous consequences in microglia, namely lipid accumulation and immune activation. This provides a new non-cell-autonomous approach to alleviate neuroinflammatory states, which accompany many neurodegenerative diseases. It will be interesting to explore whether these same mechanisms are at play in other neurodegenerative diseases that display lipid accumulation, including α-synucleinopathies and APOE4-linked diseases (Fanning et al., 2019).
Multiple studies have profiled how microglial lipid accumulation impacts neurons—both their signaling activity and tau phosphorylation (Haney et al., 2024; Victor et al., 2022)—as well as astrocyte reactivity (Guttenplan et al., 2021), but Li et al. flip that paradigm to show how neuronal lipids lead to lipid accumulation and inflammatory activation in microglia. Together, these studies paint a picture of neuronal and microglial lipid accumulation feeding bidirectionally to create a perfect pathological storm. However, this study from Li et al. offers one way to target neurons and perhaps break this cycle.
References:
Fanning S, Haque A, Imberdis T, Baru V, Barrasa MI, Nuber S, Termine D, Ramalingam N, Ho GP, Noble T, Sandoe J, Lou Y, Landgraf D, Freyzon Y, Newby G, Soldner F, Terry-Kantor E, Kim TE, Hofbauer HF, Becuwe M, Jaenisch R, Pincus D, Clish CB, Walther TC, Farese RV Jr, Srinivasan S, Welte MA, Kohlwein SD, Dettmer U, Lindquist S, Selkoe D. Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment. Mol Cell. 2019 Mar 7;73(5):1001-1014.e8. Epub 2018 Dec 4 PubMed.
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Haney MS, Pálovics R, Munson CN, Long C, Johansson PK, Yip O, Dong W, Rawat E, West E, Schlachetzki JC, Tsai A, Guldner IH, Lamichhane BS, Smith A, Schaum N, Calcuttawala K, Shin A, Wang YH, Wang C, Koutsodendris N, Serrano GE, Beach TG, Reiman EM, Glass CK, Abu-Remaileh M, Enejder A, Huang Y, Wyss-Coray T. APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia. Nature. 2024 Apr;628(8006):154-161. Epub 2024 Mar 13 PubMed.
Prakash P, Manchanda P, Paouri E, Bisht K, Sharma K, Wijewardhane PR, Randolph CE, Clark MG, Fine J, Thayer EA, Crockett A, Gasmi N, Stanko S, Prayson RA, Zhang C, Davalos D, Chopra G. Amyloid β Induces Lipid Droplet-Mediated Microglial Dysfunction in Alzheimer's Disease. bioRxiv. 2023 Jun 6; PubMed.
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Victor MB, Leary N, Luna X, Meharena HS, Scannail AN, Bozzelli PL, Samaan G, Murdock MH, von Maydell D, Effenberger AH, Cerit O, Wen HL, Liu L, Welch G, Bonner M, Tsai LH. Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity. Cell Stem Cell. 2022 Aug 4;29(8):1197-1212.e8. PubMed.
View all comments by Priyanka NarayanUniversity of Pennsylvania
Accumulation of lipids in glia was first noted as a hallmark of Alzheimer’s disease when it was first described over 100 years ago, but only recently has there been a number of studies characterizing this phenomenon at a molecular and mechanistic level (Marschallinger et al., 2020; Sienski et al., 2021; Claes et al., 2021; Victor et al., 2022; Prakash et al., 2023; Windham et al., 2023; Haney et al., 2024). A common thread of these studies is that these lipid accumulations are lipid droplets (LDs) found primarily in microglia but also astrocytes and that these cells have a dysfunctional or damaging phenotype. Lipid-droplet-accumulating glia have been described in the context of brain injury, brain aging, and neurodegenerative disease. In the context of Alzheimer’s disease, recent studies have used amyloid models to show that an inflammatory microglial response to amyloid plaques could be a driver of lipid-droplet-accumulating microglia (LDAM) (Prakash et al., 2023; Haney et al., 2024).
This study from Li et al. is exciting because it illustrates that similar lipid droplet accumulations occur in a tauopathy mouse model (PS19), with the highest proportion of LDs, 70 percent, observed in microglia. The lipid droplet-accumulating microglia are mostly observed near phospho-tau pathology. Consistent with previous reports, the LD-accumulating microglia show increased inflammatory cytokines and impaired phagocytosis. A great aspect of this study is the authors pair deuterium oxide (D2O) labeling with Raman scattering (SRS) microscopy in fly models and in vitro cell culture models to trace lipid turnover and transfer between cells. This is very exciting because there is likely a high degree of transfer of these accumulating lipids between glial cells to neurons and vice-versa, but this is difficult to measure. The authors show that in iPSCs lines with an FTD-associated V337M tau mutation, neurons transfer lipids to microglia and induce microglial LD accumulation, pro-inflammatory responses, and impaired phagocytosis, a cellular phenotype of LDAM consistent with previous reports (Marschallinger et al., 2020).
This is interesting because it has always been a bit of a mystery as to what is the source of the lipids that accumulate in microglia under these conditions. There could be cell-autonomous or non-cell-autonomous causes for lipid accumulation or a combination of both. Previous reports have shown that innate immune triggers, such as LPS or fibrillar Ab are sufficient to induce lipid droplets in vitro and in vivo (Marschallinger et al., 2020; Prakash et al., 2023; Haney et al., 2024) and there are also reports indicating that phagocytosed myelin debris is a major source of lipid accumulation in microglia in models of demyelination (Nugent et al., 2020; Cantuti-Castelvetri el al., 2018). This study adds a new source—neurons—as a cause of lipid droplet accumulating microglia in neurodegeneration.
Given the cellular complexity of the CNS and how neurodegenerative diseases unfold over long periods of time, all these mechanisms could be occurring sequentially, or simultaneously, and bi-directionally. Questions remain as to the mechanisms and timing of how these lipids are trafficked between these cell types and about which cell types are resilient versus vulnerable to these lipids. Excitingly, this study concludes by showing that, through targeting AMPK, lipid levels can be reduced through autophagy, and microglial state and function restored, which is consistent with similar approaches to lower lipid droplet levels through autophagy related pathways (Haney et al., 2024). This indicates, that while there is much to be learned about the cellular mechanisms underlying lipid accumulation and trafficking in neurodegenerative disease, pharmacological interventions could revert these cellular states and restore function.
References:
Marschallinger J, Iram T, Zardeneta M, Lee SE, Lehallier B, Haney MS, Pluvinage JV, Mathur V, Hahn O, Morgens DW, Kim J, Tevini J, Felder TK, Wolinski H, Bertozzi CR, Bassik MC, Aigner L, Wyss-Coray T. Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat Neurosci. 2020 Feb;23(2):194-208. Epub 2020 Jan 20 PubMed. Correction.
Claes C, Danhash EP, Hasselmann J, Chadarevian JP, Shabestari SK, England WE, Lim TE, Hidalgo JL, Spitale RC, Davtyan H, Blurton-Jones M. Plaque-associated human microglia accumulate lipid droplets in a chimeric model of Alzheimer's disease. Mol Neurodegener. 2021 Jul 23;16(1):50. PubMed.
Victor MB, Leary N, Luna X, Meharena HS, Scannail AN, Bozzelli PL, Samaan G, Murdock MH, von Maydell D, Effenberger AH, Cerit O, Wen HL, Liu L, Welch G, Bonner M, Tsai LH. Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity. Cell Stem Cell. 2022 Aug 4;29(8):1197-1212.e8. PubMed.
Sienski G, Narayan P, Bonner JM, Kory N, Boland S, Arczewska AA, Ralvenius WT, Akay L, Lockshin E, He L, Milo B, Graziosi A, Baru V, Lewis CA, Kellis M, Sabatini DM, Tsai LH, Lindquist S. APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia. Sci Transl Med. 2021 Mar 3;13(583) PubMed.
Windham IA, Ragusa JV, Wallace ED, Wagner CH, White KK, Cohen S. APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size. bioRxiv. 2023 Apr 29; PubMed.
Prakash P, Manchanda P, Paouri E, Bisht K, Sharma K, Wijewardhane PR, Randolph CE, Clark MG, Fine J, Thayer EA, Crockett A, Gasmi N, Stanko S, Prayson RA, Zhang C, Davalos D, Chopra G. Amyloid β Induces Lipid Droplet-Mediated Microglial Dysfunction in Alzheimer's Disease. bioRxiv. 2023 Jun 6; PubMed.
Haney MS, Pálovics R, Munson CN, Long C, Johansson PK, Yip O, Dong W, Rawat E, West E, Schlachetzki JC, Tsai A, Guldner IH, Lamichhane BS, Smith A, Schaum N, Calcuttawala K, Shin A, Wang YH, Wang C, Koutsodendris N, Serrano GE, Beach TG, Reiman EM, Glass CK, Abu-Remaileh M, Enejder A, Huang Y, Wyss-Coray T. APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia. Nature. 2024 Apr;628(8006):154-161. Epub 2024 Mar 13 PubMed.
Nugent AA, Lin K, van Lengerich B, Lianoglou S, Przybyla L, Davis SS, Llapashtica C, Wang J, Kim DJ, Xia D, Lucas A, Baskaran S, Haddick PC, Lenser M, Earr TK, Shi J, Dugas JC, Andreone BJ, Logan T, Solanoy HO, Chen H, Srivastava A, Poda SB, Sanchez PE, Watts RJ, Sandmann T, Astarita G, Lewcock JW, Monroe KM, Di Paolo G. TREM2 Regulates Microglial Cholesterol Metabolism upon Chronic Phagocytic Challenge. Neuron. 2020 Mar 4;105(5):837-854.e9. Epub 2020 Jan 2 PubMed.
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View all comments by Michael HaneyMcLean Hospital/Harvard Medical School
Harvard Medical School
Using sophisticated SRS (stimulated Raman scattering) imaging analyses combined with mouse and fly tauopathy in vivo models, or in vitro in human neurons carrying a V337M Tau mutation, the authors show that tauopathy is associated with an accumulation of lipid droplets in microglia and human neurons, and that pathways for lipid synthesis (lipogenesis) are increased and lipid mobilization is decreased. Moreover, microglial cells in vitro accumulated lipids, and increased inflammatory cytokine production, when exposed to conditioned media from V337M tau human neurons. Based on the analysis of AMP-AD RNA-Seq datasets, the authors found a downregulation of PRKAA (which encodes the alpha subunit of AMPK), in AD brain. Genetic and pharmacological manipulation of AMPK pathways using both in vitro and in vivo approaches demonstrated AMPK regulation of lipid droplets in neurons and microglia, and of inflammatory molecules. Using AMPK activation or inhibition/deletion as tools to manipulate lipid turnover, the findings highlight that targeting pathways that cause lipid accumulations in various cell types in neurodegenerative diseases is an important field for therapeutic development.
A key finding of this study is the demonstration that tauopathy, lipid disturbances, and neuroinflammation are highly interconnected. Our point of view is that microglial activation occurs in many different neurodegenerative diseases, and we have shown that neuroinflammation and complement activation is associated with brain lipid accumulation (Rocha et al., 2015; Connolly et al., 2023). We and others have also shown that lipid abnormalities, including those associated with aging, precede protein accumulation and neuronal degeneration (Rocha et al., 2015; Brekk et al., 2020; Cooper et al., 2024).
It is not clear why lipids accumulate in the tauopathy models, although lipid droplet accumulation is observed in human neurons following a-synuclein overexpression (Fanning et al., 2019). One consideration not discussed, and sometimes overlooked, is the critical normal function of tau in microtubule stabilization and intracellular transport, on which neurons depend. Indeed, tau abnormalities and axonal transport deficits are central to many neurodegenerative diseases.
Another question to consider is why the expression of PRKAA is decreased in the brain in AD. This could be a physiological adaptation and part of a network of feedback mechanisms in response to metabolic and lipid disturbances in the AD brain, which becomes pathological over time.
Overall, this elegant work highlights the complex lipid networks that are at the core of AD, PD, LBD, and FTD, and highlights the need for us to understand these systems and intervene in a meaningful way for patients.
References:
Brekk OR, Korecka JA, Crapart CC, Huebecker M, MacBain ZK, Rosenthal SA, Sena-Esteves M, Priestman DA, Platt FM, Isacson O, Hallett PJ. Upregulating β-hexosaminidase activity in rodents prevents α-synuclein lipid associations and protects dopaminergic neurons from α-synuclein-mediated neurotoxicity. Acta Neuropathol Commun. 2020 Aug 6;8(1):127. PubMed.
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View all comments by Ole IsacsonUniversity of Pennsylvania
I’m excited about these findings, which bolster the growing body of work that neurons transfer lipids to glia, most likely to alleviate their own oxidative damage, and that lipids accumulate in Alzheimer’s brains. The role for AMPK described here is intriguing, although, as the authors note, this can have varied effects. While astrocytes can also be recipients of lipids from neurons, it appears that in the context of neurodegeneration at least, microglia dominate. How microglia normally process those lipids remains a question of interest.
View all comments by Amita SehgalMake a Comment
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