Abstract
Antibodies have been explored extensively as a potential therapeutic for Alzheimer’s disease, where amyloid-β (Aβ) peptides and the tau protein deposit in patient brains. While the major focus of antibody-based therapy development was on Aβ, arguably with limited success in clinical trials, targeting tau has become an emerging strategy, possibly extending therapies to dementias with isolated tau pathology. Interestingly, low titres of autoantibodies to pathological tau have been described in humans and transgenic mouse models, but their pathophysiological relevance remained elusive. Here, we used two independent approaches to deplete the B-cell lineage and hence antibody formation in human P301S mutant tau transgenic mice, TAU58/2. TAU58/2 mice were either crossed with the B-cell-deficient Ighm knockout line (muMT−/−) or treated with anti-CD20 antibodies that target B-cell precursors. In both models, B-cell depletion significantly reduced astrocytosis in TAU58/2 mice. Only when B-cells were absent throughout life, in TAU58/2.muMT−/− mice, were spatial learning deficits moderately aggravated while motor performance improved as compared to B-cell-competent TAU58/2 mice. This was associated with changes in brain region-specific tau solubility. No other relevant behavioural or neuropathological changes were observed in TAU58/2 mice in the absence of B-cells/antibodies. Taken together, our data suggests that the presence of antibodies throughout life contributes to astrocytosis in TAU58/2 mice and limits learning deficits, while other deficits and neuropathological changes appear to be independent of the presence of B-cells/antibodies.
Highlights
Dementia, including its most common form, Alzheimer’s disease (AD), is one of the major causes of disability affecting older people, with an estimated 50 million people living with a form of dementia globally
To determine a possible contribution of antibodies to phenotype and pathology of TAU58/2 mice, we first crossed them with muMT−/− mice (Fig. 1a). muMT−/− mice have a targeted disruption in transmembrane region of the Ighm gene encoding the heavy chain segment of IgM antibodies which are expressed on the surface membrane at the pre-B lymphocyte stage of cell d evelopment[23]
Fluorescence-activated cell sorting (FACS) of spleens from TAU58/2.muMT−/− confirmed a lack of IgM+/B220high lymphocytes, suggesting arrest of B lymphocyte development at the pre-B lymphocyte phase in these mice (Fig. 1c,d)
Summary
Dementia, including its most common form, Alzheimer’s disease (AD), is one of the major causes of disability affecting older people, with an estimated 50 million people living with a form of dementia globally. This includes the TAU58/2 line more recently developed by us; TAU58/2 mice express human P301S mutant tau in neurons and present with progressive tau hyperphosphorylation and NFT pathology, as well as early-onset motor, behavioural and learning deficits[17] Using such transgenic mouse models, tau has been extensively targeted pre-clinically in both active and passive immunization approaches, showing efficacy in reducing tau pathology and in some studies improving cognitive and behavioural deficits[18,19]. We crossed TAU58/2 mice with B-cell-deficient m uMT−/− mice or depleted B-cells in young TAU58/2 mice using anti-CD20 antibodies to explore the role of the adaptive immune system, antibodies and attributable neuroinflammation, in the context of tau pathology This augmented learning deficits of TAU58/2 mice while astrocytosis was reduced, suggesting a contribution of antibodies to disease onset and progression. This knowledge may improve understanding of the connection between antibodies and tau in disease
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