Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies

Borislav Dejanovic; Melanie A. Huntley; Ann De Mazière; William J. Meilandt; Tiffany Wu; Karpagam Srinivasan; Zhiyu Jiang; Vineela Gandham; Brad A. Friedman; Hai Ngu; Oded Foreman; Richard A.D. Carano; Ben Chih; Judith Klumperman; Corey Bakalarski; Jesse E. Hanson; Morgan Sheng

doi:10.1016/j.neuron.2018.10.014

Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies

Borislav Dejanovic^*, Melanie A. Huntley, Ann De Mazière, William J. Meilandt, Tiffany Wu, Karpagam Srinivasan, Zhiyu Jiang, Vineela Gandham, Brad A. Friedman, Hai Ngu, Oded Foreman, Richard A.D. Carano, Ben Chih, Judith Klumperman, Corey Bakalarski, Jesse E. Hanson, Morgan Sheng

^*Corresponding author for this work

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

2 Citations (Scopus)

Abstract

Synapse loss and Tau pathology are hallmarks of Alzheimer's disease (AD) and other tauopathies, but how Tau pathology causes synapse loss is unclear. We used unbiased proteomic analysis of postsynaptic densities (PSDs) in Tau-P301S transgenic mice to identify Tau-dependent alterations in synapses prior to overt neurodegeneration. Multiple proteins and pathways were altered in Tau-P301S PSDs, including depletion of a set of GTPase-regulatory proteins that leads to actin cytoskeletal defects and loss of dendritic spines. Furthermore, we found striking accumulation of complement C1q in the PSDs of Tau-P301S mice and AD patients. At synapses, C1q decorated perisynaptic membranes, accumulated in correlation with phospho-Tau, and was associated with augmented microglial engulfment of synapses and decline of synapse density. A C1q-blocking antibody inhibited microglial synapse removal in cultured neurons and in Tau-P301S mice, rescuing synapse density. Thus, inhibiting complement-mediated synapse removal by microglia could be a potential therapeutic target for Tau-associated neurodegeneration.

Original language	English
Pages (from-to)	1322-1336.e7
Journal	Neuron
Volume	100
Issue number	6
DOIs	https://doi.org/10.1016/j.neuron.2018.10.014
Publication status	Published - 19 Dec 2018

Keywords

Alzheimer's disease
C1q
complement
GTPase
mass spectrometry
neurodegeneration
postsynaptic density
proteomics
synapse
Tau
Embryo, Mammalian
Post-Synaptic Density/metabolism
Humans
Proteome/metabolism
Synapses/drug effects
Female
Cell Differentiation
Tauopathies/diagnostic imaging
Complement C1q/immunology
Animals, Newborn
Prion Proteins/genetics
Mutation/genetics
Mice, Inbred C57BL
Cells, Cultured
Rats
Induced Pluripotent Stem Cells/drug effects
Mice, Transgenic
Antibodies/therapeutic use
tau Proteins/genetics
Animals
Amyloid beta-Protein Precursor/genetics
Mice
Presenilin-2/genetics

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10.1016/j.neuron.2018.10.014

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Dejanovic, B., Huntley, M. A., De Mazière, A., Meilandt, W. J., Wu, T., Srinivasan, K., Jiang, Z., Gandham, V., Friedman, B. A., Ngu, H., Foreman, O., Carano, R. A. D., Chih, B., Klumperman, J., Bakalarski, C., Hanson, J. E., & Sheng, M. (2018). Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies. Neuron, 100(6), 1322-1336.e7. https://doi.org/10.1016/j.neuron.2018.10.014

@article{88e618e96f6e44caa1e2230026ecc1be,

title = "Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies",

abstract = "Synapse loss and Tau pathology are hallmarks of Alzheimer's disease (AD) and other tauopathies, but how Tau pathology causes synapse loss is unclear. We used unbiased proteomic analysis of postsynaptic densities (PSDs) in Tau-P301S transgenic mice to identify Tau-dependent alterations in synapses prior to overt neurodegeneration. Multiple proteins and pathways were altered in Tau-P301S PSDs, including depletion of a set of GTPase-regulatory proteins that leads to actin cytoskeletal defects and loss of dendritic spines. Furthermore, we found striking accumulation of complement C1q in the PSDs of Tau-P301S mice and AD patients. At synapses, C1q decorated perisynaptic membranes, accumulated in correlation with phospho-Tau, and was associated with augmented microglial engulfment of synapses and decline of synapse density. A C1q-blocking antibody inhibited microglial synapse removal in cultured neurons and in Tau-P301S mice, rescuing synapse density. Thus, inhibiting complement-mediated synapse removal by microglia could be a potential therapeutic target for Tau-associated neurodegeneration.",

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author = "Borislav Dejanovic and Huntley, {Melanie A.} and {De Mazi{\`e}re}, Ann and Meilandt, {William J.} and Tiffany Wu and Karpagam Srinivasan and Zhiyu Jiang and Vineela Gandham and Friedman, {Brad A.} and Hai Ngu and Oded Foreman and Carano, {Richard A.D.} and Ben Chih and Judith Klumperman and Corey Bakalarski and Hanson, {Jesse E.} and Morgan Sheng",

year = "2018",

month = dec,

day = "19",

doi = "10.1016/j.neuron.2018.10.014",

language = "English",

volume = "100",

pages = "1322--1336.e7",

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Dejanovic, B, Huntley, MA, De Mazière, A, Meilandt, WJ, Wu, T, Srinivasan, K, Jiang, Z, Gandham, V, Friedman, BA, Ngu, H, Foreman, O, Carano, RAD, Chih, B, Klumperman, J, Bakalarski, C, Hanson, JE & Sheng, M 2018, 'Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies', Neuron, vol. 100, no. 6, pp. 1322-1336.e7. https://doi.org/10.1016/j.neuron.2018.10.014

TY - JOUR

T1 - Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies

AU - Dejanovic, Borislav

AU - Huntley, Melanie A.

AU - De Mazière, Ann

AU - Meilandt, William J.

AU - Wu, Tiffany

AU - Srinivasan, Karpagam

AU - Jiang, Zhiyu

AU - Gandham, Vineela

AU - Friedman, Brad A.

AU - Ngu, Hai

AU - Foreman, Oded

AU - Carano, Richard A.D.

AU - Chih, Ben

AU - Klumperman, Judith

AU - Bakalarski, Corey

AU - Hanson, Jesse E.

AU - Sheng, Morgan

PY - 2018/12/19

Y1 - 2018/12/19

N2 - Synapse loss and Tau pathology are hallmarks of Alzheimer's disease (AD) and other tauopathies, but how Tau pathology causes synapse loss is unclear. We used unbiased proteomic analysis of postsynaptic densities (PSDs) in Tau-P301S transgenic mice to identify Tau-dependent alterations in synapses prior to overt neurodegeneration. Multiple proteins and pathways were altered in Tau-P301S PSDs, including depletion of a set of GTPase-regulatory proteins that leads to actin cytoskeletal defects and loss of dendritic spines. Furthermore, we found striking accumulation of complement C1q in the PSDs of Tau-P301S mice and AD patients. At synapses, C1q decorated perisynaptic membranes, accumulated in correlation with phospho-Tau, and was associated with augmented microglial engulfment of synapses and decline of synapse density. A C1q-blocking antibody inhibited microglial synapse removal in cultured neurons and in Tau-P301S mice, rescuing synapse density. Thus, inhibiting complement-mediated synapse removal by microglia could be a potential therapeutic target for Tau-associated neurodegeneration.

AB - Synapse loss and Tau pathology are hallmarks of Alzheimer's disease (AD) and other tauopathies, but how Tau pathology causes synapse loss is unclear. We used unbiased proteomic analysis of postsynaptic densities (PSDs) in Tau-P301S transgenic mice to identify Tau-dependent alterations in synapses prior to overt neurodegeneration. Multiple proteins and pathways were altered in Tau-P301S PSDs, including depletion of a set of GTPase-regulatory proteins that leads to actin cytoskeletal defects and loss of dendritic spines. Furthermore, we found striking accumulation of complement C1q in the PSDs of Tau-P301S mice and AD patients. At synapses, C1q decorated perisynaptic membranes, accumulated in correlation with phospho-Tau, and was associated with augmented microglial engulfment of synapses and decline of synapse density. A C1q-blocking antibody inhibited microglial synapse removal in cultured neurons and in Tau-P301S mice, rescuing synapse density. Thus, inhibiting complement-mediated synapse removal by microglia could be a potential therapeutic target for Tau-associated neurodegeneration.

KW - Alzheimer's disease

KW - C1q

KW - complement

KW - GTPase

KW - mass spectrometry

KW - neurodegeneration

KW - postsynaptic density

KW - proteomics

KW - synapse

KW - Tau

KW - Embryo, Mammalian

KW - Post-Synaptic Density/metabolism

KW - Humans

KW - Proteome/metabolism

KW - Synapses/drug effects

KW - Female

KW - Cell Differentiation

KW - Tauopathies/diagnostic imaging

KW - Complement C1q/immunology

KW - Animals, Newborn

KW - Prion Proteins/genetics

KW - Mutation/genetics

KW - Mice, Inbred C57BL

KW - Cells, Cultured

KW - Rats

KW - Induced Pluripotent Stem Cells/drug effects

KW - Mice, Transgenic

KW - Antibodies/therapeutic use

KW - tau Proteins/genetics

KW - Animals

KW - Amyloid beta-Protein Precursor/genetics

KW - Mice

KW - Presenilin-2/genetics

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U2 - 10.1016/j.neuron.2018.10.014

DO - 10.1016/j.neuron.2018.10.014

M3 - Article

C2 - 30392797

AN - SCOPUS:85057592336

SN - 0896-6273

VL - 100

SP - 1322-1336.e7

JO - Neuron

JF - Neuron

IS - 6

ER -

Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies

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