Antibody Repertoire Modulation Alters Alzheimer’s Pathology and Behavior in the 5XFAD Mouse Model 2267871

Abstract

Alzheimer’s Disease (AD) is one of the most prominent neurodegenerative diseases. The disease is associated with amyloid-β (Aβ) accumulation, protein tau neurofibrillary tangles, neuronal loss, and chronic inflammation in the brain. Aβ plaque accumulation leads to an inflammatory response orchestrated by resident microglia and ultimately neurodegeneration. Recent literature suggests that the immune system, particularly antibodies, plays a key role in disease progression. We sought to characterize the role of specific antibodies in AD by manipulating the repertoire of the 5XFAD model system. We crossed MD4 mice, which have a B cell repertoire restricted to an irrelevant antigen, with 5XFAD mice, which model early onset Alzheimer’s disease, to address whether specific antibodies modulate disease progression. These mice underwent a battery of behavioral tests to measure cognitive impairment, followed by tissue collection for analysis of plaque accumulation, microglia activation, and antibody deposition by immunohistochemistry (IHC). Analysis of 5XFAD brains using monoclonal antibodies specific for IgG subclasses revealed an increase in microglia-associated IgG1 within the hippocampus compared to non-transgenic littermates. MD4 5XFAD double transgenic mice had sex specific increases in cognitive impairment, including increased mobility in the open field, nighttime hyperactivity, and decreased spontaneous alternation in a cross-maze compared to 5XFAD littermates. By IHC, we detected a modest trending increase in amyloid-β plaque accumulation at 10 months of age in double transgenic mice compared to 5xFAD brain. The wildtype and MD4 mice brains did not display any amyloid-β plaque accumulation, as expected. Our results suggest that specific antibodies restrict the progression of cognitive impairment in 5XFAD mice. Ongoing work is aimed at uncovering the specificities and origin of the spontaneous antibodies that can be found within the brains of 5XFAD mice. The National Institute of Health (NIH) Neuroimmunology (NEUR)