Objective: to investigate the role of PLA2 in neuronal development and in memory processing, as well as the relationship between membrane phospholipid abnormalities and certain clinical and biological aspects of AD.
Materials and Methods: In vitro studies: the activity of cytosolic PLA2a was determined with the aid of a radio-enzymatic method. In pre-term embryonic rat brains, PLA2 activity was ascertained in cortical, hippocampal and total brain homogenates. In primary cultures of cortical neurons, PLA2 activity was sequentially determined along with the maturation of cells. Inhibition and activation curves of PLA2 activity in neurons were obtained respectively by the treatment of cells with MAFP and mellitin. Animal studies: adult rats were bilaterally implanted with indwelling cannulae in the CA1 region of the dorsal hippocampus. Animals received bilateral infusion of saline or inhibitory doses of MAFP before being submitted to step-down inhibitory avoidance training, and were tested for short- and long-term memory. Clinical studies: AD patients and controls were cognitively assessed by the MMSE and the CAMDEX schedule. Subjects were drug-free for at least 2 weeks. PLA2 activity was determined in platelet membranes, and intracerebral phospholipid metabolism was addressed with the aid of 31P-spectroscopy. Spectral curves of phosphate-containing molecules (PME, PDE, ATP) were obtained within a 40cm3 voxel addressing the pre-frontal cortex.
Results: In the embryonic rat brain, PLA2 activity gradually decreases toward birth, without significant differences regarding different topographies. In vitro, neuronal PLA2 activity peaks between the 3rd and 6th days in culture. MAFP inhibited PLA2 activity at optimal concentrations of 100-250mM. Mellitin activated PLA2 in a dose-dependent fashion. In vivo, PLA2 inhibition impaired both short- and long-term memory processing of the inhibitory avoidance, without affecting locomotor activity and exploratory behaviour. In platelet membranes, PLA2 activity was significantly lower in AD than controls. Lower PLA2 activity correlated with a worse cognitive performance, particularly in memory and attention tasks. PME resonance and PME/PDE ratio were higher among AD patients, and PDE values were lower. No significant differences were found in ATP, PC and IP resonance. Negative correlations were found between PME and cognitive performance, namely total CAMCOG and MMSE scores, as well as in memory, orientation, visual perception, and abstract thinking sub-scores.
Conclusion: cPLA2a is activated during the maturation of cultures, suggesting its involvement in neuronal development and survival. PLA2 participates in memory processing in the CA1 region of rat hippocampus. Reduced platelet PLA2 activity and abnormal phospholipid turnover in AD correlate with cognitive deficits.
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