Alzheimer’s disease (AD) is characterized by the accumulation of two pathological hallmarks in brain areas mediating cognitive function: 1) extracellular senile plaques consisting of aggregated amyloid-beta peptides and 2) intracellular neurofibrillary tangles (NFTs) composed of fibrillar aggregates of the protein tau. Although NFT pathology is strongly linked to neurodegeneration and cognitive decline in AD, several lines of evidence indicate that it is the soluble “pre-tangle” aggregates of tau formed prior to NFTs that are the neurotoxic species driving disease progression resulting in cognitive impairment. In this study, we aimed to quantify pre-tangle tau moieties in the cognitive brain regions that falter the earliest in AD to advance our understanding of disease mechanisms and test if pre-tangle tau pathology associates with cognitive decline. We examined postmortem tissue from three brain regions–frontal cortex (FC), posterior cingulate cortex (PCC), and precuneus (PreC)–that form functionally connected Default Mode Network (DMN), which shows altered functional connectivity in patients with subjective cognitive decline (SCD) as well as with mild cognitive impairment (MCI) who later convert to frank AD. Immunohistochemical and biochemical quantification of pre-tangle tau by epitope-specific antibodies (pS422, TOC1, TNT2, and TauC3) indicated that pathological tau was present in the low Braak stages in the DMN, and its level significantly increased between the transition from Braak stage IV to Braak stage V. The pre-tangle tau pathology also demonstrated a tight and inverse correlation with several antemortem cognitive test scores, including those related to global cognition, episodic and semantic memory, as well as with postmortem neuropathological diagnostic scores. We also found possible regional differences in pre-tangle tau load among those three brain regions, with PCC showing higher pathology compared to its neighboring region, PreC. To further investigate the tau protein interactome that may underlie the regional difference in pre-tangle tau pathology burden, we performed a co-immunoprecipitation of pathological tau and its protein binding partners for mass spectrometric analysis. The results revealed that tau interactions within PCC and PreC were associated with different stress response to AD pathology, while PCC demonstrated abnormally elevated lipid metabolism and immune activation. Collectively, our findings contribute to the timeline of pre-tangle tau accumulation in the DMN network in AD with a potential regional difference for the pathology load between the two posterior hubs. We also found a close and inverse correlation between the pre-tangle tau and cognitive decline, emphasizing the potential of the study to develop effective disease-mitigating strategies.
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