Regional AT-8 reactive tau species correlate with intracellular A levels in cases of low AD neuropathologic change

The amyloid cascade hypothesis states that A beta aggregates induce pathological changes in tau, leading to neurofibrillary tangles (NFTs) and cell death. A caveat with this hypothesis is the spatio-temporal divide between plaques and NFTs. This has been addressed by the inclusion of soluble A beta and tau species in the revised amyloid cascade hypothesis. Nevertheless, despite the potential for non-plaque A beta to contribute to tau pathology, few studies have examined relative correlative strengths between total A beta, plaque A beta and intracellular A beta with tau pathology within a single tissue cohort. Employing frozen and fixed frontal cortex grey and white matter tissue from non-AD controls (Con; n = 39) and Alzheimer's disease (AD) cases (n = 21), biochemical and immunohistochemical (IHC) measures of A beta and AT-8 phosphorylated tau were assessed. Biochemical native-state dot blots from crude tissue lysates demonstrated robust correlations between total A beta and AT-8 tau, when considered as a combined cohort (Con and AD) and when as Con and AD cases, separately. In contrast, no associations between A beta plaques and AT-8 were reported when using IHC measurements in either Con or AD cases. However, when intracellular A beta was measured via the A beta specific antibody MOAB-2, a correlative relationship with AT-8 tau was reported in non-AD controls but not in AD cases. Collectively the data suggests that accumulating intracellular A beta may influence AT-8 pathology, early in AD-related neuropathological change. Despite the lower levels of phospho-tau and A beta in controls, the robust correlative relationships observed suggest a physiological association of A beta production and tau phosphorylation, which may be modified during disease. This study is supportive of a revised amyloid cascade hypothesis and demonstrates regional associative relationships between tau pathology and intracellular A beta, but not extracellular A beta plaques.