Tau Aggregate Imaging and Transcriptomics of Alzheimer's Disease Brain at Different Stages of Disease

Tau aggregation plays a critical role in the development and progression of Alzheimer's disease (AD). Tau aggregates of different sizes and shapes are formed, which ultimately lead to the deposition of fibrillar tangles. We used single-molecule techniques to characterize tau aggregates in the middle temporal gyrus and somatosensory cortex in post-mortem brain homogenates at different Braak stages from patients with AD. Total and phosphorylated tau aggregates increased dramatically in late Braak stages. The aggregates showed greater multi-site phosphorylation with increased Braak stage, but there was only a moderate change in the aggregate size distribution. Paired single nuclei transcriptomic analyses provided evidence for greater pro-inflammatory microglial and complement pathway activation with increasing phosphorylated tau aggregate concentration and length. Based on this correlation, we hypothesize a cascade of disease progression in which microglial inflammation induces tau aggregation in neighboring neurons that, in turn, further enhances inflammation and the spread of tau pathology to increase the concentration of small tau aggregates.