The role of B-cells and antibodies in Alzheimer’s disease
Creators: name: van der Hoven, Julia
Publisher: name: Macquarie University
Year: 2023
Subjects: classificationCode: 399999
subject: Other education not elsewhere classified

description: Alzheimer’s disease (AD) is the most prevalent form of a group of neurodegenerative disorders termed dementias. It is characterised by intracellular neurofibrillary tangles, composed of hyperphosphorylated protein tau, and extracellular amyloid-β plaques. It is estimated that approximately 30 million people are currently affected by AD worldwide, with approximately 95% of cases considered to be sporadic (not hereditary), affecting predominantly aging populations 65 years of age and older. Thus, AD presents a substantial socio-economic burden to the world population. The increase in prevalence of dementia however is greater than the rate of aging population growth, suggesting alternative contributors to AD pathogenesis. Immunotherapy as a preventative or curative treatment for AD has been, and continues to be, fervently investigated. Translation to clinical success has been limited, however many clinical trials are currently ongoing. The use of antibodies, or antigens that stimulate antibody production in B cells in these vaccination/immunization trials might be more successful if the mechanisms involved in antibody-mediated processes were better understood. Furthermore, antibodies against tau and amyloid-β have been found in untreated humans – young and old, with AD and healthy individuals – as well as in unvaccinated AD transgenic mouse lines. The function of these endogenous antibodies remains unknown. Thus, this body of work aims to determine whether B cells and endogenous antibodies play a role in AD pathogenesis and/or progression and to investigate the mechanisms involved. Crossing the TAU58/2 or APP23 mouse lines, which model pathology of the two AD hallmark proteins (tau and Aβ, respectively), with the B cell-deficient muMT mouse line (genetic ablation) or treatment with α-CD20 antibodies (depletion) to remove mature B cells and antibodies allowed for <em>in vivo </em>investigation of processes in AD mouse models in the presence or absence of B-cells and antibodies at various timepoints. The first part of this thesis explores the role that B-cells and antibodies play in the pathogenesis of AD in the context of pathological tau, utilizing the TAU58/2 mouse model which expresses human tau with a P301S mutation and presents with tau pathology and cognitive and behavioural deficits at an early age. Astrocytosis was significantly reduced in both genetic ablation and depletion experiments in TAU58/2 mice and only when B cells were absent throughout life in the TAU58/2.muMT-/- mice were changes in behavioural and motor deficits observed. Although there were no specifically affected species of tau, both methods of B-cell depletion could induce changes in tau solubility throughout several brain regions. The second part of the thesis describes the same experimental methods in the APP23 mouse line. This mouse model overexpresses human amyloid precursor protein (APP) harbouring a pathological mutation and the mice present with cognitive deficits and increased mortality. In the APP23 mice there appears to be several antibody- (or B cell-) mediated mechanisms at play at different ages affecting survival and protein levels in the presence of amyloid-β. It was also discovered that transfer of immunity, in the form of B-cells and antibodies, from mothers to offspring produces a longlasting protective effect. In conclusion, while further research into the mechanisms behind the observations in this body of work is required, B-cells and endogenous antibodies are capable of modulating pathological proteins and phenotypes in mouse models of AD. Furthermore, these results suggest that different effects appear to be mediated by antibodies or B-cells or these components in combination and that specific timepoints exist at which these mouse models are more susceptible to effects mediated by B-cells and antibodies.