In-situ characterization of Alzheimer's disease tau aggregates via super-resolution imaging.

Abstract

Alzheimer's disease (AD) is among the most common and devastating neurological disorders. One of the pathological hallmarks of AD is the appearance of morphologically heterogenous insoluble aggregates made up of the microtubule-associated protein tau. The emergence of tau aggregates at distinct brain regions strongly correlates with clinical symptoms and neuropathological features. These observations suggest that tau aggregation has a crucial and toxic role in AD. Tau's native functions are regulated through the phosphorylation and dephosphorylation of specific residues. Previous studies indicate that insoluble tau aggregates (e.g., neurofibrillary tangles) contain abnormally hyperphosphorylated tau. However, the precise link between the pattern and degree of tau hyperphosphorylation and aggregation remains unclear. Using multicolor DNA-PAINT super-resolution microscopy in human postmortem AD brain tissues, I have mapped specific tau residues that are hyperphosphorylated within tau aggregates, particularly tau oligomers (20-30 nm), which are thought to seed tau aggregation. Preliminary results show that multiple tau residues, including early (phospho-Thr231) and late (phospho-Ser202/Thr205) tau aggregation phosphorylation markers, are enriched within oligomeric tau seeds. In contrast, these phospho-tau marks are differentially enriched within linear and branched tau fibrils. These results suggest that hyperphosphorylation at distinct tau residues may template the aggregation of tau into distinct tau aggregate species. Overall, this work has the potential to facilitate the development of therapies that can accurately target various tau aggregates through the identification of the specific molecular signatures of tau seeds and tau aggregates present in human pathology.