Are early stage tau depositions associated with pyroglutamylated Aβ in Alzheimer’s disease?

Abstract Background Hallmark lesions observed Alzheimer’s disease (AD) include neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein (HP‐ T ) and amyloid β plaques. Pyroglutamylated Aβ (pAβ) is a sub‐species of Aβ, and we have previously demonstrated an association between (pAβ) and HP‐ T in human post‐mortem brains, and observed that pAβ predicts the severity of clinical dementia. Several studies in transgenic mouse models have demonstrated Aβ inducing HP‐ T pathology and anti‐Aβ antibody treatment eliminated not only parenchymal Aβ deposits but also early stage HP‐ T deposits while mature NFTs remained unaltered suggesting that Aβ ‐ HP‐ T interaction takes place at an early stage of NFT development. However, these studies did not specifically look for the proportion of pAβ within Aβ and hence data on the interaction between pAβ and stages of NFT development are lacking. We now aim to investigate whether pAβ is associated with tau conformations that represent earlier stages of tangle development, measured by MC1 and CP13 antibodies in human post‐mortem tissue. Method Tissue from frontal, temporal, parietal, occipital and entorhinal cortices from 70 post‐mortem brains (35 AD and 35 aged controls) were processed into a tissue microarray blocks for high throughput analysis, and stained for pAβ, MC1, and CP13. Percentage area of immunopositivity calculated using an automated image analysis system. Result pAβ, MC1, and CP13 loads were higher in AD cases compared to controls in all regions (all p < 0.05). The burden of pAβ positively correlated with the burden of MC1 and CP13 in all regions (all p < 0.05). Conclusion This study provides the first set of results from a larger screening study to determine at which point the interaction between pAβ and tau takes place. Our results suggests pAβ is associated with conformational states of tau that represent early stage tau depositions. Therefore studies investigating whether immunisation using pAβ is capable of removing early stage tau depositions, precluding excessive mature NFT tau accumulations, and attenuating cognitive decline in AD are warranted.