New Mouse Models to Study the Role of Complement in Brain Aging and Neurodegeneration

Qiaoqiao Shi, PhD
Brigham and Women's Hospital, Harvard Medical School (Boston, MA)

Mentors

Cynthia Lemere, PhD
Brigham and Women's Hospital, Harvard Medical School
Year Awarded:
2016
Grant Duration:
July 1, 2016 to June 30, 2018
Disease:
Alzheimer's Disease
Award Amount:
$100,000
Grant Reference ID:
A2016425F
Award Type:
Postdoctoral Fellowship
Award Region:
US Northeastern

This grant is made possible in part by a bequest from the Estate of Frederick J. Pelda.

Qiaoqiao Shi, PhD

Characterization of Novel C3 Conditional Knockout Mice: Tools to Better Understand the Role of Complement in Synaptic Dysfunction in Aging and Alzheimer’s Disease

Summary

Complement component 3 (C3) is an immune molecule that helps to refine the visual system during brain development by removing weak synapses, or connections between nerves. C3 is up-regulated in Alzheimer’s disease (AD) and therefore may contribute to the synapse loss that underlies cognitive decline. We recently reported that aged mice lacking C3 throughout life have preserved synapses and better memory than normal-aged mice. To further understand when and where C3 plays a role in AD, we have generated two novel mouse models in which C3 gene expression can be shut off at any age by injection of a chemical, or deleted in specific immune cells (only) throughout life. Further characterization of these mice will better define the role of C3 in the aging brain and AD and may direct us to new therapies.

Details

Complement component 3 (C3) helps mediate synaptic elimination during the development of the mouse brain and is upregulated in Alzheimer’s disease (AD), a condition in which synaptic loss is an early event. Recently, we reported that aged C3 knockout mice were protected against age- and brain region-dependent synapse and neuron loss, and had superior cognitive performance compared to age-matched normal mice (Shi et al, J Neurosci, 2015). Therefore, we recently generated two novel C3 conditional knockout mouse models in which C3 expression can be “shut off” at any age by tamoxifen injection, or deleted in all myeloid immune cells (only) throughout life, to distinguish C3’s effects on brain development versus aging and neurodegeneration. I will use high-resolution confocal microscopy to quantify structural synapses and novel microglia-specific antibodies to determine the effects of post-development global C3 deletion or myeloid-specific C3 deletion in these newly generated mice at different ages. In addition, I will crossbreed one of our C3 cKO mouse lines with AD mice to generate the first-ever, AD mouse model in which C3 expression can be deleted at any age. 

About the Researcher

I began studying the role of the immune system and inflammation in aging and Alzheimer’s disease (AD) when I joined Dr. Cindy Lemere’s lab at Harvard’s Brigham & Women’s Hospital, six years ago. I am the lead investigator for Dr. Lemere’s project that focuses on the role of complement in synapse loss during aging and AD, utilizing complement C3- and CR3- deficient mice. Throughout my studies, I have observed significant age-related differences in synapses, neurons, microglia, and behavior between male C57BL/6 WT mice vs. C3 knockout (KO) and CR3 KO mice. My studies involve the use of immunohistochemistry, high-resolution confocal microscopy, stereology, electrophysiology, biochemical quantification of synaptic proteins, and behavioral techniques. These long-term studies, examining mice at three different ages, are now coming to fruition and will soon result in several publications, the first of which was recently published by the Journal of Neuroscience as a featured article (Shi et al, J Neurosci, 2015).  Further, under Dr. Lemere’s NIH R21 grant, I generated C3 conditional KO (cKO) mice with C3flox/flox mice (generated under our NIH R21 by Dr. Michael Carroll, our collaborator) to investigate the effects of C3 deletion after brain development and in mice that constitutively lack C3 in all myeloid cells. These novel mouse models provide meaningful tools to elucidate the possible mechanisms by which the immune system and complement, in particular, play a role in the brain during aging and/or neurodegenerative diseases. I look forward to characterizing our C3 cKO mice and performing the initial crossbreeding to generate a C3 cKO AD mouse model to begin to investigate the effects of post-development global C3-deletion on synapse dysfunction and AD pathogenesis.

Personal Story

I began studying the role of the immune system and inflammation in aging and Alzheimer’s disease (AD) when I joined Dr. Cynthia Lemere’s lab at the Ann Romney Center of Neurologic Diseases, six years ago. I lead Dr. Lemere’s project focusing on the role of complement in synapse loss during aging and AD utilizing complement C3-deficient mice. These long-term studies, examining mice at three ages, have resulted in several publications, the first of which was published in the Journal of Neuroscience. This work, on which I was first author, attracted significant attention and were mentioned in the editor’s commentary in “This Week in the Journal.”

In addition, I tested the effects of C3 deficiency in an AD mouse model and found lifelong C3 deficiency protected neurons against age- and AD-related changes by altering the glial response to amyloid-beta plaques, which protected against cognitive decline. This manuscript, on which I am the first author, is currently under revision at Science Translational Medicine. Another paper related to this study, on which I am a co-author, was recently published in Science by our collaborators in the [Beth] Stevens lab at Children’s Hospital Boston (Hong et al, Science, 2016).

Under Dr. Lemere’s NIH R21 grant, I generated two C3 conditional KO (cKO) mouse models described above, which serve as meaningful tools for our research into the role of C3 in aging and in neurodegeneration. My fellowship from BrightFocus Foundation will permit me to continue this important investigation into how the immune system interacts with the brain during aging and AD pathogenesis. I thank BrightFocus Foundation for providing me with the opportunity conduct this research into an area which ultimately may provide novel therapies for AD.

Publications

Shi Q, Chowdhury S, Ma R, Le KX, Hong S, Caldarone BJ, Stevens B, Lemere CA. Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci Transl Med. 2017 May 31;9(392). pii: eaaf6295. doi: 10.1126/scitranslmed.aaf6295. PubMed PMID: 28566429. PubMed Icon Google Scholar Icon

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