Graduation Year

2017

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medical Sciences

Major Professor

Dave Morgan, Ph.D.

Committee Member

Marcia Gordon, Ph.D.

Committee Member

Edwin Weeber, Ph.D.

Committee Member

Paula Bickford, Ph.D.

Keywords

Tauopathy, rTg4510, Treatment, Pathology, Behavior

Abstract

Alzheimer’s disease (AD) is the leading cause of dementia, accounting for 50 to 80 percent of dementia cases, and the prevalence of the disease is projected to increase significantly with time. AD is characterized by severe cognitive decline with age, ultimately requiring continued caregiving and eventually death. The pathology of AD is characterized by the presence of extracellular amyloid plaques, intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated tau protein, neuron loss, and evidence of inflammation indicated by the presence of reactive microglia and astrocytes. Frontotemporal Lobe Dementia (FTLD) is a rare form of dementia that is related to AD, most notably in the pathology of hyperphosphorylated tau and macroscopic brain shrinkage. It has been defined as one of a host of tauopathies, and has a more rapid onset than AD. Symptoms that resemble personality changes, moreso than memory loss, are characteristic of these other tauopathies (FTLD is a representative of a whole class of neurological disorders). Like AD, there are no known treatments or cures for FTLD. AD and FTLD are two manifestations of a class of diseases known as tauopathies, due to the presence of toxic forms of tau.

Tau is a protein normally found in neurons. It functions as a stabilizer for microtubules, and has a role in the trafficking of materials from the cell body to the presynaptic terminal. In AD and FTLD, tau can become hyperphosphorylated, which causes it to form twisted fibrils called NFTs. An emerging area of research is to identify antibodies that target tau as a way to clear tau pathology and hopefully reduce synaptic and neuron loss (Boutajangout et al., 2011b). While these diseases have no known cure or treatment at present, immunotherapy is emerging as a promising approach for treatment. The studies presented here investigated a variety of antibodies directed against tau, and incorporated different timeframes and administration routes to identify the best candidate for future clinical investigation of tau immunotherapy.

The mouse model rTg4510, known for expressing cognitive-related tauopathy, was primarily used to evaluate tau antibody effectiveness prior to clinical consideration. Our investigations began by utilizing a more familiar mouse which was also reported to express tau pathology.

Our studies first examined intracranial injection of a variety of antibodies using a mouse model previously reported to demonstrate tau pathology, to identify short-term clearance of tau pathology and NFTs. Next, we examined a more robust tau-producing mouse line, to further identify a most effective antibody, as well as to examine the time course of effect, after administration. A longer-term administration, and different route of administration was tested using mini-osmotic pump implantation into the mice, which provided for 28-day continuous infusion. This approach was followed with administration of antibodies, systemically. Behavioral analysis, in addition to pathological testing, was incorporated into the longer-term administration studies.

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