APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia
© 2024. The Author(s)..
Several genetic risk factors for Alzheimer's disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells1. However, the relationship between lipid metabolism in glia and Alzheimer's disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer's disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer's disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aβ induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer's disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer's disease.
| Errataetall: | |
|---|---|
| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:628 |
|---|---|
| Enthalten in: |
Nature - 628(2024), 8006 vom: 12. Apr., Seite 154-161 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Haney, Michael S [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
ACSL1 protein, human |
|---|
| Anmerkungen: |
Date Completed 05.04.2024 Date Revised 06.04.2024 published: Print-Electronic UpdateOf: bioRxiv. 2023 Jul 25;:. - PMID 37546938 Citation Status MEDLINE |
|---|
| doi: |
10.1038/s41586-024-07185-7 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM369705882 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM369705882 | ||
| 003 | DE-627 | ||
| 005 | 20240406232305.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240315s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41586-024-07185-7 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1367.xml |
| 035 | |a (DE-627)NLM369705882 | ||
| 035 | |a (NLM)38480892 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Haney, Michael S |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 05.04.2024 | ||
| 500 | |a Date Revised 06.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a UpdateOf: bioRxiv. 2023 Jul 25;:. - PMID 37546938 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024. The Author(s). | ||
| 520 | |a Several genetic risk factors for Alzheimer's disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells1. However, the relationship between lipid metabolism in glia and Alzheimer's disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer's disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer's disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aβ induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer's disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer's disease | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Amyloid beta-Peptides |2 NLM | |
| 650 | 7 | |a Apolipoprotein E4 |2 NLM | |
| 650 | 7 | |a ACSL1 protein, human |2 NLM | |
| 650 | 7 | |a EC 6.2.1.3 |2 NLM | |
| 650 | 7 | |a Triglycerides |2 NLM | |
| 650 | 7 | |a tau Proteins |2 NLM | |
| 650 | 7 | |a Culture Media, Conditioned |2 NLM | |
| 700 | 1 | |a Pálovics, Róbert |e verfasserin |4 aut | |
| 700 | 1 | |a Munson, Christy Nicole |e verfasserin |4 aut | |
| 700 | 1 | |a Long, Chris |e verfasserin |4 aut | |
| 700 | 1 | |a Johansson, Patrik K |e verfasserin |4 aut | |
| 700 | 1 | |a Yip, Oscar |e verfasserin |4 aut | |
| 700 | 1 | |a Dong, Wentao |e verfasserin |4 aut | |
| 700 | 1 | |a Rawat, Eshaan |e verfasserin |4 aut | |
| 700 | 1 | |a West, Elizabeth |e verfasserin |4 aut | |
| 700 | 1 | |a Schlachetzki, Johannes C M |e verfasserin |4 aut | |
| 700 | 1 | |a Tsai, Andy |e verfasserin |4 aut | |
| 700 | 1 | |a Guldner, Ian Hunter |e verfasserin |4 aut | |
| 700 | 1 | |a Lamichhane, Bhawika S |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, Amanda |e verfasserin |4 aut | |
| 700 | 1 | |a Schaum, Nicholas |e verfasserin |4 aut | |
| 700 | 1 | |a Calcuttawala, Kruti |e verfasserin |4 aut | |
| 700 | 1 | |a Shin, Andrew |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yung-Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Chengzhong |e verfasserin |4 aut | |
| 700 | 1 | |a Koutsodendris, Nicole |e verfasserin |4 aut | |
| 700 | 1 | |a Serrano, Geidy E |e verfasserin |4 aut | |
| 700 | 1 | |a Beach, Thomas G |e verfasserin |4 aut | |
| 700 | 1 | |a Reiman, Eric M |e verfasserin |4 aut | |
| 700 | 1 | |a Glass, Christopher K |e verfasserin |4 aut | |
| 700 | 1 | |a Abu-Remaileh, Monther |e verfasserin |4 aut | |
| 700 | 1 | |a Enejder, Annika |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Yadong |e verfasserin |4 aut | |
| 700 | 1 | |a Wyss-Coray, Tony |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Nature |d 1945 |g 628(2024), 8006 vom: 12. Apr., Seite 154-161 |w (DE-627)NLM000008257 |x 1476-4687 |7 nnns |
| 773 | 1 | 8 | |g volume:628 |g year:2024 |g number:8006 |g day:12 |g month:04 |g pages:154-161 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41586-024-07185-7 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 628 |j 2024 |e 8006 |b 12 |c 04 |h 154-161 | ||