Pyroglutamylated amyloid-β is associated with hyperphosphorylated tau and severity of Alzheimer's disease

Pyroglutamylated amyloid-beta (pE(3)-A beta) has been suggested to play a major role in Alzheimer's disease (AD) pathogenesis as amyloid-beta (A beta) oligomers containing pE(3)-A beta might initiate tau-dependent cytotoxicity. We aimed to further elucidate the associations among pE(3)-A beta, full-length A beta and hyperphosphorylated tau (HP-tau) in human brain tissue. We examined 41 post mortem brains of both AD (n = 18) and controls. Sections from frontal and entorhinal cortices were stained with pE(3)-A beta, HP-tau and full-length A beta antibodies. The respective loads were assessed using image analysis and western blot analysis was performed in a subset of cases. All loads were significantly higher in AD, but when using A beta loads as independent variables only frontal pE(3)-A beta load predicted AD. In frontal and entorhinal cortices pE(3)-A beta load independently predicted HP-tau load while non-pE(3)-A beta failed to do so. All loads correlated with the severity of AD neuropathology. However, partial correlation analysis revealed respective correlations in the frontal cortex only for pE(3)-A beta load only while in the entorhinal cortex respective correlations were seen for both HP-tau and non-pE(3)-A beta loads. Mini Mental State Examination scores were independently predicted by entorhinal HP-tau load and by frontal pE(3)-A beta load. Here, we report an association between pE(3)-A beta and HP-tau in human brain tissue and an influence of frontal pE(3)-A beta on both the severity of AD neuropathology and clinical dementia. Our findings further support the notion that pE(3)-A beta may represent an important link between A beta and HP-tau, and investigations into its role as diagnostic and therapeutic target in AD are warranted.