Basic Science and Pathogenesis.

Background: Beta-2 microglobulin (β2m) is a component of the major histocompatibility complex class I (MHC-I) playing a crucial role in the immune system on cell surface, but it can be separated from the MHC-I and exist in biological fluid independently. Numerous reports have shown that β2m is a systemic pro-aging factor impairing cognitive function, and that it is increased in the blood and CSF of patients with Alzheimer's disease (AD). While β2m in the body fluid has been recognized as a potential factor in AD and aging, the development of therapeutic agents, especially those directly targeting β2m using antibodies, may face challenges.

Monoclonal antibody Y01 prevents tauopathy progression induced by lysine 280-acetylated tau in cell and mouse models.

The spatiotemporal pattern of the spread of pathologically modified tau through brain regions in Alzheimer's disease (AD) can be explained by prion-like cell-to-cell seeding and propagation of misfolded tau aggregates. Hence, to develop targeted therapeutic antibodies, it is important to identify the seeding- and propagation-competent tau species. The hexapeptide 275VQIINK280 of tau is a critical region for tau aggregation, and K280 is acetylated in various tauopathies, including AD.

Tau acetylation at K280 regulates tau phosphorylation.

Purpose/aim Of The Study: Accumulation of hyperphosphorylated tau is a key pathological finding of Alzheimer's disease. Recently, acetylation of tau is emerging as another key pathogenic modification, especially regarding the acetylation of tau at K280 of the hexapeptide VQIINK, a critical sequence in driving tau aggregation. However, the relationship between these two key post-translational modifications is not well known.