A frontal variant of Alzheimer's disease exhibits decreased calcium-independent phospholipase A2 activity in the prefrontal cortex

A frontal variant of Alzheimer's disease (AD) has recently been identified on neuropathological and neuropsychological grounds (Johnson, J.K., Head, E ., Kim, R., Starr, A., Cotman, C.W., 1999. Clinical and pathological eviden ce for a frontal variant of Alzheimer Disease. Arch. Neurol. 56, 1233-1239) . Frontal AD differs strikingly from typical AD by the occurrence of neurof ibrillary tangle densities in the frontal cortex as high or higher than in the entorhinal cortex. Since cerebrocortical membranes are commonly abnorma l in Alzheimer's disease (AD), we assayed frontal AD cases for enzymes regu lating membrane phospholipid composition. We specifically measured activity of phospholipase A2s (PLA2s) in dorsolateral prefrontal and lateral tempor al cortices of frontal AD cases (n = 12), which have respectively high and low densities of neurofibrillary tangles. In neither cortical area was Ca2-dependent PLA2 activity abnormal compared to controls (n = 12). In contras t, a significant 42% decrease in Ca2+-independent PLA2 activity was found i n the dorsolateral prefrontal, but not the lateral temporal, cortex of the frontal AD cases. Similarly, the dorsolateral prefrontal cortex, but not th e lateral temporal cortex of the frontal AD cases suffered a 42% decrease i n total free fatty acid content, though neither that decrease nor those in any one species of free fatty acid was significant. The observed biochemica l changes probably occurred in neurons given (a) our finding that PLA2 acti vity of cultured human NT2 neurons is virtually all Ca2+-independent and (b ) the finding of others that nearly all Ca2+-independent PLA2 in brain gray matter is neuronal. The decrease in Ca2+-independent PLA2 activity is not readily attributable to Group VI or VIII iPLA2s since neither NT2N neurons nor our brain homogenates were greatly inhibited by drugs potently suppress ing those iPLA2s. Decreased Ca2+-independent PLA2 activity in frontal AD ma y reflect a compensatory response to pathologically accelerated phospholipi d metabolism early in the disorder. That could cause an early elevation of prefrontal free fatty acids, which can stimulate polymerization of tau and thus promote the prefrontal neurofibrillary tangle formation characteristic of frontal AD. (C) 2000 Elsevier Science Ltd. All rights reserved.