Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer's disease mouse models

Borislav Dejanovic; Tiffany Wu; Ming-Chi Tsai; David Graykowski; Vineela D Gandham; Christopher M Rose; Corey E Bakalarski; Hai Ngu; Yuanyuan Wang; Shristi Pandey; Mitchell G Rezzonico; Brad A Friedman; Rose Edmonds; Ann De Mazière; Raphael Rakosi-Schmidt; Tarjinder Singh; Judith Klumperman; Oded Foreman; Michael C Chang; Luke Xie; Morgan Sheng; Jesse E Hanson

doi:10.1038/s43587-022-00281-1

Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer's disease mouse models

Borislav Dejanovic, Tiffany Wu, Ming-Chi Tsai, David Graykowski, Vineela D Gandham, Christopher M Rose, Corey E Bakalarski, Hai Ngu, Yuanyuan Wang, Shristi Pandey, Mitchell G Rezzonico, Brad A Friedman, Rose Edmonds, Ann De Mazière, Raphael Rakosi-Schmidt, Tarjinder Singh, Judith Klumperman, Oded Foreman, Michael C Chang, Luke XieMorgan Sheng, Jesse E Hanson

Research output: Contribution to journal › Article › Academic › peer-review

1 Downloads (Pure)

Abstract

Microglia and complement can mediate neurodegeneration in Alzheimer's disease (AD). By integrative multi-omics analysis, here we show that astrocytic and microglial proteins are increased in Tau P301S synapse fractions with age and in a C1q-dependent manner. In addition to microglia, we identified that astrocytes contribute substantially to synapse elimination in Tau P301S hippocampi. Notably, we found relatively more excitatory synapse marker proteins in astrocytic lysosomes, whereas microglial lysosomes contained more inhibitory synapse material. C1q deletion reduced astrocyte-synapse association and decreased astrocytic and microglial synapses engulfment in Tau P301S mice and rescued synapse density. Finally, in an AD mouse model that combines β-amyloid and Tau pathologies, deletion of the AD risk gene Trem2 impaired microglial phagocytosis of synapses, whereas astrocytes engulfed more inhibitory synapses around plaques. Together, our data reveal that astrocytes contact and eliminate synapses in a C1q-dependent manner and thereby contribute to pathological synapse loss and that astrocytic phagocytosis can compensate for microglial dysfunction.

Original language	English
Pages (from-to)	837-850
Number of pages	14
Journal	Nature Aging
Volume	2
Issue number	9
DOIs	https://doi.org/10.1038/s43587-022-00281-1
Publication status	Published - Sept 2022

Keywords

Alzheimer Disease/genetics
Animals
Astrocytes/metabolism
Complement C1q/genetics
Membrane Glycoproteins/metabolism
Mice
Microglia/metabolism
Receptors, Immunologic/metabolism
Synapses/metabolism

Access to Document

10.1038/s43587-022-00281-1Licence: CC BY

s43587-022-00281-1Final published version, 20.2 MBLicence: CC BY

Cite this

Dejanovic, B., Wu, T., Tsai, M.-C., Graykowski, D., Gandham, V. D., Rose, C. M., Bakalarski, C. E., Ngu, H., Wang, Y., Pandey, S., Rezzonico, M. G., Friedman, B. A., Edmonds, R., De Mazière, A., Rakosi-Schmidt, R., Singh, T., Klumperman, J., Foreman, O., Chang, M. C., ... Hanson, J. E. (2022). Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer's disease mouse models. Nature Aging, 2(9), 837-850. https://doi.org/10.1038/s43587-022-00281-1

@article{2afa4dd5d9da4d18a99776e6921bdbca,

title = "Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer's disease mouse models",

abstract = "Microglia and complement can mediate neurodegeneration in Alzheimer's disease (AD). By integrative multi-omics analysis, here we show that astrocytic and microglial proteins are increased in Tau P301S synapse fractions with age and in a C1q-dependent manner. In addition to microglia, we identified that astrocytes contribute substantially to synapse elimination in Tau P301S hippocampi. Notably, we found relatively more excitatory synapse marker proteins in astrocytic lysosomes, whereas microglial lysosomes contained more inhibitory synapse material. C1q deletion reduced astrocyte-synapse association and decreased astrocytic and microglial synapses engulfment in Tau P301S mice and rescued synapse density. Finally, in an AD mouse model that combines β-amyloid and Tau pathologies, deletion of the AD risk gene Trem2 impaired microglial phagocytosis of synapses, whereas astrocytes engulfed more inhibitory synapses around plaques. Together, our data reveal that astrocytes contact and eliminate synapses in a C1q-dependent manner and thereby contribute to pathological synapse loss and that astrocytic phagocytosis can compensate for microglial dysfunction. ",

keywords = "Alzheimer Disease/genetics, Animals, Astrocytes/metabolism, Complement C1q/genetics, Membrane Glycoproteins/metabolism, Mice, Microglia/metabolism, Receptors, Immunologic/metabolism, Synapses/metabolism",

author = "Borislav Dejanovic and Tiffany Wu and Ming-Chi Tsai and David Graykowski and Gandham, {Vineela D} and Rose, {Christopher M} and Bakalarski, {Corey E} and Hai Ngu and Yuanyuan Wang and Shristi Pandey and Rezzonico, {Mitchell G} and Friedman, {Brad A} and Rose Edmonds and {De Mazi{\`e}re}, Ann and Raphael Rakosi-Schmidt and Tarjinder Singh and Judith Klumperman and Oded Foreman and Chang, {Michael C} and Luke Xie and Morgan Sheng and Hanson, {Jesse E}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = sep,

doi = "10.1038/s43587-022-00281-1",

language = "English",

volume = "2",

pages = "837--850",

number = "9",

}

Dejanovic, B, Wu, T, Tsai, M-C, Graykowski, D, Gandham, VD, Rose, CM, Bakalarski, CE, Ngu, H, Wang, Y, Pandey, S, Rezzonico, MG, Friedman, BA, Edmonds, R, De Mazière, A, Rakosi-Schmidt, R, Singh, T, Klumperman, J, Foreman, O, Chang, MC, Xie, L, Sheng, M & Hanson, JE 2022, 'Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer's disease mouse models', Nature Aging, vol. 2, no. 9, pp. 837-850. https://doi.org/10.1038/s43587-022-00281-1

TY - JOUR

T1 - Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer's disease mouse models

AU - Dejanovic, Borislav

AU - Wu, Tiffany

AU - Tsai, Ming-Chi

AU - Graykowski, David

AU - Gandham, Vineela D

AU - Rose, Christopher M

AU - Bakalarski, Corey E

AU - Ngu, Hai

AU - Wang, Yuanyuan

AU - Pandey, Shristi

AU - Rezzonico, Mitchell G

AU - Friedman, Brad A

AU - Edmonds, Rose

AU - De Mazière, Ann

AU - Rakosi-Schmidt, Raphael

AU - Singh, Tarjinder

AU - Klumperman, Judith

AU - Foreman, Oded

AU - Chang, Michael C

AU - Xie, Luke

AU - Sheng, Morgan

AU - Hanson, Jesse E

PY - 2022/9

Y1 - 2022/9

N2 - Microglia and complement can mediate neurodegeneration in Alzheimer's disease (AD). By integrative multi-omics analysis, here we show that astrocytic and microglial proteins are increased in Tau P301S synapse fractions with age and in a C1q-dependent manner. In addition to microglia, we identified that astrocytes contribute substantially to synapse elimination in Tau P301S hippocampi. Notably, we found relatively more excitatory synapse marker proteins in astrocytic lysosomes, whereas microglial lysosomes contained more inhibitory synapse material. C1q deletion reduced astrocyte-synapse association and decreased astrocytic and microglial synapses engulfment in Tau P301S mice and rescued synapse density. Finally, in an AD mouse model that combines β-amyloid and Tau pathologies, deletion of the AD risk gene Trem2 impaired microglial phagocytosis of synapses, whereas astrocytes engulfed more inhibitory synapses around plaques. Together, our data reveal that astrocytes contact and eliminate synapses in a C1q-dependent manner and thereby contribute to pathological synapse loss and that astrocytic phagocytosis can compensate for microglial dysfunction.

AB - Microglia and complement can mediate neurodegeneration in Alzheimer's disease (AD). By integrative multi-omics analysis, here we show that astrocytic and microglial proteins are increased in Tau P301S synapse fractions with age and in a C1q-dependent manner. In addition to microglia, we identified that astrocytes contribute substantially to synapse elimination in Tau P301S hippocampi. Notably, we found relatively more excitatory synapse marker proteins in astrocytic lysosomes, whereas microglial lysosomes contained more inhibitory synapse material. C1q deletion reduced astrocyte-synapse association and decreased astrocytic and microglial synapses engulfment in Tau P301S mice and rescued synapse density. Finally, in an AD mouse model that combines β-amyloid and Tau pathologies, deletion of the AD risk gene Trem2 impaired microglial phagocytosis of synapses, whereas astrocytes engulfed more inhibitory synapses around plaques. Together, our data reveal that astrocytes contact and eliminate synapses in a C1q-dependent manner and thereby contribute to pathological synapse loss and that astrocytic phagocytosis can compensate for microglial dysfunction.

KW - Alzheimer Disease/genetics

KW - Animals

KW - Astrocytes/metabolism

KW - Complement C1q/genetics

KW - Membrane Glycoproteins/metabolism

KW - Mice

KW - Microglia/metabolism

KW - Receptors, Immunologic/metabolism

KW - Synapses/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85138436598&partnerID=8YFLogxK

U2 - 10.1038/s43587-022-00281-1

DO - 10.1038/s43587-022-00281-1

M3 - Article

C2 - 37118504

VL - 2

SP - 837

EP - 850

JO - Nature Aging

JF - Nature Aging

IS - 9

ER -

Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer's disease mouse models

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this