TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss

Rosa C Paolicelli, Ali Jawaid, Christopher M. Henstridge, Andrea Valeri, Mario Merlini, John L Robinson, Edward B Lee, Jamie Rose, Stanley Appel, Virginia M-Y Lee, John Q Trojanowski, Tara Spires-Jones, Paul E Schulz, Lawrence Rajendran

Research output: Contribution to journalArticle

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Abstract

Microglia coordinate various functions in the central nervous system ranging from removing synaptic connections, to maintaining brain homeostasis by monitoring neuronal function, and clearing protein aggregates across the lifespan. Here we investigated whether increased microglial phagocytic activity that clears amyloid can also cause pathological synapse loss. We identified TDP-43, a DNA-RNA binding protein encoded by the Tardbp gene, as a strong regulator of microglial phagocytosis. Mice lacking TDP-43 in microglia exhibit reduced amyloid load in a model of Alzheimer's disease (AD) but at the same time display drastic synapse loss, even in the absence of amyloid. Clinical examination from TDP-43 pathology cases reveal a considerably reduced prevalence of AD and decreased amyloid pathology compared to age-matched healthy controls, confirming our experimental results. Overall, our data suggest that dysfunctional microglia might play a causative role in the pathogenesis of neurodegenerative disorders, critically modulating the early stages of cognitive decline.
Original languageEnglish
Pages (from-to)297-308.e6
Number of pages12
JournalNeuron
Volume95
Issue number2
DOIs
Publication statusPublished - 19 Jul 2017

Fingerprint

Microglia
Amyloid
Synapses
Alzheimer Disease
Pathology
RNA-Binding Proteins
DNA-Binding Proteins
Phagocytosis
Neurodegenerative Diseases
Homeostasis
Central Nervous System
Brain
Genes

Keywords

  • TDP-43
  • Tardbp
  • Microglia
  • Phagocytosis
  • Synaptic Pruning
  • Synapse Loss
  • Amyloid
  • Clearance
  • Alzheimer’s Disease
  • Frontotemporal Lobar Degeneration
  • Amyotrophic Lateral Sclerosis

Cite this

Paolicelli, R. C., Jawaid, A., Henstridge, C. M., Valeri, A., Merlini, M., Robinson, J. L., ... Rajendran, L. (2017). TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss. Neuron, 95(2), 297-308.e6. https://doi.org/10.1016/j.neuron.2017.05.037
Paolicelli, Rosa C ; Jawaid, Ali ; Henstridge, Christopher M. ; Valeri, Andrea ; Merlini, Mario ; Robinson, John L ; Lee, Edward B ; Rose, Jamie ; Appel, Stanley ; Lee, Virginia M-Y ; Trojanowski, John Q ; Spires-Jones, Tara ; Schulz, Paul E ; Rajendran, Lawrence. / TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss. In: Neuron. 2017 ; Vol. 95, No. 2. pp. 297-308.e6.
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Paolicelli, RC, Jawaid, A, Henstridge, CM, Valeri, A, Merlini, M, Robinson, JL, Lee, EB, Rose, J, Appel, S, Lee, VM-Y, Trojanowski, JQ, Spires-Jones, T, Schulz, PE & Rajendran, L 2017, 'TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss', Neuron, vol. 95, no. 2, pp. 297-308.e6. https://doi.org/10.1016/j.neuron.2017.05.037

TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss. / Paolicelli, Rosa C; Jawaid, Ali; Henstridge, Christopher M.; Valeri, Andrea; Merlini, Mario; Robinson, John L; Lee, Edward B; Rose, Jamie; Appel, Stanley; Lee, Virginia M-Y; Trojanowski, John Q; Spires-Jones, Tara; Schulz, Paul E; Rajendran, Lawrence.

In: Neuron, Vol. 95, No. 2, 19.07.2017, p. 297-308.e6.

Research output: Contribution to journalArticle

TY - JOUR

T1 - TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss

AU - Paolicelli, Rosa C

AU - Jawaid, Ali

AU - Henstridge, Christopher M.

AU - Valeri, Andrea

AU - Merlini, Mario

AU - Robinson, John L

AU - Lee, Edward B

AU - Rose, Jamie

AU - Appel, Stanley

AU - Lee, Virginia M-Y

AU - Trojanowski, John Q

AU - Spires-Jones, Tara

AU - Schulz, Paul E

AU - Rajendran, Lawrence

PY - 2017/7/19

Y1 - 2017/7/19

N2 - Microglia coordinate various functions in the central nervous system ranging from removing synaptic connections, to maintaining brain homeostasis by monitoring neuronal function, and clearing protein aggregates across the lifespan. Here we investigated whether increased microglial phagocytic activity that clears amyloid can also cause pathological synapse loss. We identified TDP-43, a DNA-RNA binding protein encoded by the Tardbp gene, as a strong regulator of microglial phagocytosis. Mice lacking TDP-43 in microglia exhibit reduced amyloid load in a model of Alzheimer's disease (AD) but at the same time display drastic synapse loss, even in the absence of amyloid. Clinical examination from TDP-43 pathology cases reveal a considerably reduced prevalence of AD and decreased amyloid pathology compared to age-matched healthy controls, confirming our experimental results. Overall, our data suggest that dysfunctional microglia might play a causative role in the pathogenesis of neurodegenerative disorders, critically modulating the early stages of cognitive decline.

AB - Microglia coordinate various functions in the central nervous system ranging from removing synaptic connections, to maintaining brain homeostasis by monitoring neuronal function, and clearing protein aggregates across the lifespan. Here we investigated whether increased microglial phagocytic activity that clears amyloid can also cause pathological synapse loss. We identified TDP-43, a DNA-RNA binding protein encoded by the Tardbp gene, as a strong regulator of microglial phagocytosis. Mice lacking TDP-43 in microglia exhibit reduced amyloid load in a model of Alzheimer's disease (AD) but at the same time display drastic synapse loss, even in the absence of amyloid. Clinical examination from TDP-43 pathology cases reveal a considerably reduced prevalence of AD and decreased amyloid pathology compared to age-matched healthy controls, confirming our experimental results. Overall, our data suggest that dysfunctional microglia might play a causative role in the pathogenesis of neurodegenerative disorders, critically modulating the early stages of cognitive decline.

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KW - Phagocytosis

KW - Synaptic Pruning

KW - Synapse Loss

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KW - Clearance

KW - Alzheimer’s Disease

KW - Frontotemporal Lobar Degeneration

KW - Amyotrophic Lateral Sclerosis

U2 - 10.1016/j.neuron.2017.05.037

DO - 10.1016/j.neuron.2017.05.037

M3 - Article

VL - 95

SP - 297-308.e6

JO - Neuron

JF - Neuron

SN - 0896-6273

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ER -