Levels of normal and abnormally phosphorylated tau in different cellular and regional compartments of Alzheimer disease and control brains

Abstract

Microtubule associated protein tau is abnormally phosphorylated in Alzheimer disease (AD) brain. In the present study we investigated (i) whether tau is axonal or both axonal and somatodendritic, (ii) whether tau is a marker of Alzheimer neurofibrillary pathology, and (iii) whether the levels of tau in the cytosol (100,000 × g supernate) from AD brain are altered. Frozen autopsied tissue from 20 AD, 17 normal aged and 15 neurological control cases obtained 3–8 h postmortem were analyzed. Levels of normal, total, and abnormally phosphorylated tau were determined by a radioimmunoslot-blot assay using mAb Tau-1 as the primary antibody. Both frontal gray matter homogenate and cytosol from normal brains had 30–45% higher levels of normal tau than the corresponding fractions from the white matter. In AD frontal and temporal cortices, the total tau levels were 6- to 7-fold higher than in cerebellar cortex ( P < 0.01 and P < 0.02). Furthermore, tau levels of cerebellar cortex, an area of the brain unaffected with Alzheimer neurofibrillary changes, were indistinguishable between AD and control groups. The levels of normal tau in cytosol from both frontal gray and white matters in AD were reduced by approximately 40% ( P < 0.05). The levels of total tau in AD frontal and temporal cortex were 4-to 5-fold higher than in the corresponding tissue from control cases ( P < 0.01) and this increase was in the form of abnormally phosphorylated tau. These studies suggest (i) that there is probably at least as much tau in the somatodendritic compartment as in the axonal compartment, (ii) that the abnormally phosphorylated tau is a biochemical marker of the neurofibrillary pathology in AD, and (iii) that the levels of normal tau are significantly reduced in the 100,000 × g brain supernate from AD cases.