ORCID
https://orcid.org/0000-0001-5513-7758
Date of Award
Summer 8-15-2018
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Alzheimerճ (AD) disease is the most common cause of dementia and is a major public health problem for which there is currently no disease modifying therapy. Two types of protein aggregates characterize AD pathology, extracellular amyloid-_ (A_) plaques and intraneuronal tau tangles. They are accompanied by wide-spread gliosis, neuroinflammation, synaptic and neuronal loss. While these defining characteristics were described over 115 years ago, there is still a need for greater understanding of the mechanisms connecting these pathologies and how they lead to the brain atrophy and cognitive decline observed in patients. Recently, genetic studies uncovered novel sporadic AD risk variants in the microglial receptor, TREM2, which indicated the innate immune system may have a more active role in disease pathogenesis. Early studies have suggested that TREM2 facilitates microglial clustering around A_ plaques that limits surrounding neurite damage while TREM2 AD risk variants lead to a loss or reduction of function that impairs microglial signaling and is deleterious. However, the role of TREM2 in the setting of tau pathology had not yet been reported. Here, I describe how TREM2 deficiency reduced the microglial response to tau pathology, without increasing the amount of tau inclusions, which protected against neuroinflammation and brain atrophy in a mouse model of tangle deposition. Despite TREM2 function not overtly altering the amount of late-stage tau pathology, I hypothesized that plaque-associated microglia may be critical to mitigating early tau aggregation surrounding neuritic amyloid plaques. Using a newly developed paradigm for inciting the aggregation of mouse tau in mice transgenic for A_ plaque deposition, I found that less plaque-associated microglia in mice with impaired or null TREM2 function allowed for increased peri-plaque axonal dystrophy and neuritic plaque tau deposits. This novel discovery places TREM2-mediated microgliosis at the intersection of A_ and tau pathologies and, considered alongside previous studies, suggest that microglial TREM2 function is critical for preventing amyloid-dependent toxicity which may agonize initial tau pathogenesis early in AD. Yet subsequently, TREM2 enables detrimental microgliosis following the accumulation of tau pathology that can promote neurodegeneration. These findings imply dual roles for microglia in AD that are important to consider in developing potential therapies, such as antibody-directed clearance of protein aggregates. Early immunotherapeutic attempts to treat AD used monoclonal antibodies (mAbs) to reduce A_ and plaque deposition. While several A_ mAbs are still in phase 3 clinical trials for asymptomatic and prodromal patient populations, it has become clear that A_ mAbs will not provide clinically meaningful benefits for mild to moderate stage AD patients. Inability to rescue cognitive deficits in these patients is hypothesized to be because by the time individuals are in the symptomatic phase of disease, A_-related effects have peaked and tau-related pathologies are driving disease progression. The presence of tau in specific brain regions strongly correlates with cognitive decline in AD and other neurodegenerative disorders, termed tauopathies, where tau inclusions alone are linked with neurodegeneration. Thus, immunotherapeutic approaches to reduce tau aggregation are now being investigated. Previously, an anti-tau mAb, HJ8.5, was reported to reduce tau-associated pathologies in a mouse model of tauopathy, yet the mechanism of action for the mAb was still unclear. The immunoglobulin Fc domain of mAbs can bind to Fc_ receptors primarily expressed on microglia in the brain and mediates phagocytosis and clearance of the antibody-antigen complex. This binding, depending on its nature and the target, can theoretically lead to adverse effects like complement activation and the release of inflammatory cytokines that may exacerbate tau pathology and neurodegeneration. I investigated the necessity of Fc effector function for tau immunotherapy by generating full-length and truncated anti-tau HJ8.5-based constructs with differential and selective binding to Fc_ receptors. In addition, I engineered a gene therapy-based system to optimize delivery of mAbs by expressing them directly in the brain using adeno-associated virus (AAV). Using this new immunization paradigm, I saw certain anti-tau constructs without Fc effector function were still efficacious, suggesting that microglial-mediated tau clearance may not be required for anti-tau mAbs to protect against tau accumulation. However, some of my studies did not fully recapitulate the published protective effects of HJ8.5 treatment. Further optimization of technical barriers may allow for better interpretation of this data. Regardless, this AAV expression system has been successfully applied to other immunotherapy paradigms. In summary, I have demonstrated that microglia play a critical role in preventing early tau aggregation around A_ plaques, yet can promote neuroinflammation and exacerbate neurodegeneration incited by accumulating tau pathology. Anti-tau mAbs offer a way to reduce tau aggregation and this may be achieved independent of Fc effector function, though additional work is needed to better interpret collective data. Lastly, my gene therapy approach represents a plausible, long-term method for optimized delivery of full-length and truncated mAb constructs to the brain for the treatment of AD, related tauopathies, and other diseases.
Language
English (en)
Chair and Committee
David M. Holtzman
Committee Members
Heather L. True, Mark S. Sands, Timothey M. Miller, David B. Clifford,
Recommended Citation
Leyns, Cheryl Elizabeth Grace, "Loss of TREM2-dependent microgliosis in mouse models of amyloid-beta and tau pathologies reveal juxtaposed roles for reactive microglia in Alzheimerճ disease" (2018). Arts & Sciences Electronic Theses and Dissertations. 1634.
https://openscholarship.wustl.edu/art_sci_etds/1634
Comments
Permanent URL: 2020-07-31