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 evidence for a frontal variant of Alzheimer Disease. Arch. Neurol. 56, 1233-1239). Frontal AD differs strikingly from typical AD by the occurrence of neurofibrillary tangle densities in the frontal cortex as high or higher than in the entorhinal cortex. Since cerebrocortical membranes are commonly abnormal in Alzheimer's disease (AD), we assayed frontal AD cases for enzymes regulating membrane phospholipid composition. We specifically measured activity of phospholipase A2s (PLA2s) in dorsolateral prefrontal and lateral temporal cortices of frontal AD cases (n=12), which have respectively high and low densities of neurofibrillary tangles. In neither cortical area was Ca(2+)-dependent PLA2 activity abnormal compared to controls (n=12). In contrast, a significant 42% decrease in Ca(2+)-independent PLA2 activity was found in the dorsolateral prefrontal, but not the lateral temporal, cortex of the frontal AD cases. Similarly, the dorsolateral prefrontal cortex, but not the lateral temporal cortex of the frontal AD cases suffered a 42% decrease in total free fatty acid content, though neither that decrease nor those in any one species of free fatty acid was significant. The observed biochemical changes probably occurred in neurons given (a) our finding that PLA2 activity of cultured human NT2 neurons is virtually all Ca(2+)-independent and (b) the finding of others that nearly all Ca(2+)-independent PLA2 in brain gray matter is neuronal. The decrease in Ca(2+)-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 suppressing those iPLA2s. Decreased Ca(2+)-independent PLA2 activity in frontal AD may reflect a compensatory response to pathologically accelerated phospholipid 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.