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bioRxiv · 10.1101/2023.09.27.559720

Post-mortem AT-8 reactive tau species correlate with non-plaque Aβ levels in the frontal cortex of non-AD and AD brains

Malik, N.·Miah, M.·Galgani, A.·McAleese, K.·Walker, L.·LeBeau, F.·Attems, J.·Outeiro, T.·Thomas, A.·Koss, D.
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Abstract

The amyloid cascade hypothesis states that A{beta} and its aggregates induce pathological changes in tau, leading to formation of neurofibrillary tangles (NFTs) and cell death. A caveat with this hypothesis is the temporo-spatial divide between plaques and NFTs. This has been addressed by the inclusion of soluble species of A{beta} and tau in the revised amyloid cascade hypothesis, however, the demonstration of a correlative relationship between A{beta} and tau burden in post-mortem human tissue has remained elusive. Employing frozen and fixed frontal cortex grey and associated white matter tissue from non-AD controls (Con; n=39) and Alzheimers diseases (AD) cases (n=21), biochemical and immunohistochemical measures of A{beta} and AT-8 phosphorylated tau were assessed. Native-state dot-blot from crude tissue lysates demonstrated robust correlations between intraregional A{beta} and AT-8 tau, such increases in A{beta} immunoreactivity conferred increases in AT-8 immunoreactivity, both when considered across the entire cohort as well as separately in Con and AD cases. In contrast, no such association between A{beta} plaques and AT-8 were reported when using immunohistochemical measurements. However, when using the non-amyloid precursor protein cross reactive MOAB-2, antibody to measure intracellular A{beta} within a subset of cases, a similar correlative relationship with AT-8 tau as that observed in biochemical analysis was observed. Collectively our data suggests that accumulating intracellular A{beta} may influence AT-8 pathology. Despite the markedly lower levels of phospho-tau in non-AD controls correlative relationships between AT-8 phospho-tau and A{beta} as measured in both biochemical and immunohistochemical assays were more robust in non-AD controls, suggesting a physiological association of A{beta} production and tau phosphorylation, at least within the frontal cortex. Such interactions between regional A{beta} load and phospho-tau load may become modified with disease potentially, as a consequence of interregional tau seed propagation, and thus may diminish the linear relationship observed between A{beta} and phospho-tau in non-AD controls. This study provides evidence supportive of the revised amyloid cascade hypothesis, and demonstrates an associative relationship between AT-8 tau pathology and intracellular A{beta} but not extracellular A{beta} plaques.

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Malik, N., Miah, M., Galgani, A., McAleese, K., Walker, L., LeBeau, F., Attems, J., Outeiro, T., Thomas, A., Koss, D.. 2023-09-28. Post-mortem AT-8 reactive tau species correlate with non-plaque Aβ levels in the frontal cortex of non-AD and AD brains. https://doi.org/10.1101/2023.09.27.559720

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