A frontal variant of Alzheimer's disease exhibits decreased calcium-independent phospholipase A2 activity in the prefrontal cortex Konrad Talbot, Robert A. Young, Camille Jolly-Tornetta, Virginia M.-Y. Lee, John Q. Trojanowski, Bryan A. Wolf* Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA Received 16 August 1999; received in revised form 14 December 1999; accepted 17 December 1999 Abstract A frontal variant of Alzheimer's disease (AD) has recently been identi®ed 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 diers strikingly from typical AD by the occurrence of neuro®brillary 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 speci®cally 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 neuro®brillary tangles. In neither cortical area was Ca 2+ -dependent PLA2 activity abnormal compared to controls (n = 12). In contrast, a signi®cant 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 suered a 42% decrease in total free fatty acid content, though neither that decrease nor those in any one species of free fatty acid was signi®cant. The observed biochemical changes probably occurred in neurons given (a) our ®nding that PLA2 activity of cultured human NT2 neurons is virtually all Ca 2+ -independent and (b) the ®nding 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 re¯ect 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 neuro®brillary tangle formation characteristic of frontal AD. 7 2000 Elsevier Science Ltd. All rights reserved. Keywords: HELSS; Fatty acids; Frontal cortex; Human brain; NT2 neurons; Phospholipids; Temporal cortex 1. Introduction Alzheimer's disease (AD), the most common form of dementia, is marked by numerous pathological changes in the cerebral cortex, the most characteristic of which are proliferation of senile plaques and, in many cases, neuro®brillary tangles (Braak and Braak, 1994; Van Hoesen and Solodkin, 1994). Less well known, but perhaps equally important in understand- ing the pathogenesis of AD, are changes occurring in a cerebrocortical membranes. Those membranes (a) have thinner phospholipid bilayer with reduced cholesterol content (Mason et al., 1992); (b) require a lower tem- Neurochemistry International 37 (2000) 17±31 0197-0186/00/$ - see front matter 7 2000 Elsevier Science Ltd. All rights reserved. PII: S0197-0186(00)00006-1 www.elsevier.com/locate/neuint * Corresponding author. Tel.: +1-215-898-0025; fax: +1-215-573- 2266. E-mail address: wolfb@mail.med.upenn.edu (B.A. Wolf).