REDUCTION OF CALCINEURIN ENZYMATIC-ACTIVITY IN ALZHEIMERS-DISEASE - CORRELATION WITH NEUROPATHOLOGIC CHANGES

Neurofibrillary tangles (NFT), neuritic plaques, and dystrophic neurit es are the classic neuropathologic hallmarks of Alzheimer's disease (A D), all of which contain to varying degrees abnormally and/or hyperpho sphorylated forms of the microtubule-associated protein tau. Protein p hosphatase 2B (calcineurin) dephosphorylates tau isolated from AD-brai ns to control levels in vitro as well as regulates tau phosphorylation and function in vivo. It has been hypothesized that the changes in ta u phosphorylation observed in AD may be due to increases in kinase act ivity and/or decreases in phosphatase activity. In order to investigat e the latter possibility, we examined calcineurin enzyme activity usin g the substrate para-nitrophenylphosphate (pNPP) in postmortem brain s amples from individuals with moderate to severe AD (n=8) and age-match ed controls (n=7). The stimulation of calcineurin activity by manganes e chloride (1 mM) was reduced by 60% (p<0.01) in whole-cell homogenate s prepared from AD temporal cortex (Brodmann area 38). On the other ha nd, in P2 membrane fractions, the stimulation of calcineurin activity by manganese chloride as well as nickel chloride (1 mM) was reduced by 37% (p<0.05) and 79% (p<0.01), respectively. The manganese stimulated calcineurin activity in the temporal cortex inversely correlated with both the number of NFT (r=-0.60, p<0.02) and neuritic/core plaques (r =-0.63, p<0.02) in whole-cell homogenates, but only with NFT (r=-0.61, p<0.02) in P2 membrane fractions. The nickel-stimulated calcineurin a ctivity did not correlate with neuropathology measures in either whole -cell or P2 membrane fractions. In striate visual cortex (Brodmann are a 17), an area relatively unaffected in AD, neither whole-cell nor P2 membrane calcineurin activity were significantly altered. To our knowl edge, this is the first report of a reduction in calcineurin phosphata se activity in AD which correlates with the neuropathological features in a region-, subcellular fraction-, and divalent cation-specific man ner.