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Alzheimer disease (AD), a progressive neurodegenerative disorder, is the leading cause of dementia in the elderly. A combination of cholinergic and glutamatergic dysfunction appears to underlie the symptomatology of AD, and thus, treatment strategies should address impairments in both systems. Evidence suggests the involvement of phospholipase A2 (PLA2) enzyme in memory impairment and neurodegeneration in AD via actions on both cholinergic and glutamatergic systems. To review cholinergic and glutamatergic alterations underlying cognitive impairment and neuropathology in AD and attempt to link PLA2 with such alterations. Medline databases were searched (no date restrictions) for published articles with links among the terms Alzheimer disease (mild, moderate, severe), mild cognitive impairment, choline acetyltransferase, acetylcholinesterase, NGF, NGF receptor, muscarinic receptor, nicotinic receptor, NMDA, AMPA, metabotropic glutamate receptor, atrophy, glucose metabolism, phospholipid metabolism, sphingolipid, membrane fluidity, phospholipase A2, arachidonic acid, attention, memory, long-term potentiation, β-amyloid, tau, inflammation, and reactive species. Reference lists of the identified articles were checked to identify additional studies of interest. Overall, results suggest the hypothesis that persistent inhibition of cPLA2 and iPLA2 isoforms at early stages of AD may play a central role in memory deficits and β-amyloid production through down-regulation of cholinergic and glutamate receptors. As the disease progresses, β-amyloid induced up-regulation of cPLA2 and sPLA2 isoforms may play critical roles in inflammation and oxidative stress, thus participating in the neurodegenerative process. Activation and inhibition of specific PLA2 isoforms at different stages of AD could be of therapeutic importance and delay cognitive dysfunction and neurodegeneration. [ABSTRACT FROM AUTHOR]

Rationale: Phospholipase A2 (PLA2) is a family of enzymes that cleave membrane phospholipids generating important lipid mediators in signal transduction. In rat hippocampal slices, both intracellular cytosolic Ca2+-dependent PLA2 (cPLA2) and Ca2+-independent PLA2 (iPLA2) have been implicated in mechanisms of synaptic plasticity underlying memory processes. In mice, intraperitoneal injections of a selective iPLA2 inhibitor impaired spatial learning. Accordingly, reduced cPLA2 and iPLA2 activities were found in postmortem hippocampus of patients with Alzheimer's disease. Objective: This study investigates the effects of injections of PLA2 inhibitors directly into rat hippocampus on the acquisition of short-term (STM) and long-term memory (LTM) of a one-trial step-down inhibitory avoidance (IA) task. Methods: Wistar rats were bilaterally implanted with cannulae in the CA1 region of the dorsal hippocampus. After surgery, the rats received bilateral injections of a vehicle, or of dual cPLA2 and iPLA2 inhibitors (MAFP or PACOCF3), or a selective iPLA2 inhibitor (bromoenol lactone) before training in IA. The animals were tested 1.5 h (for STM) and 24 h (for LTM) after training. Results: Significant inhibition of iPLA2 activity in rat hippocampus impaired acquisition of STM and LTM. Memory impairment did not result from neuronal death after iPLA2 inhibition. Moreover, IA training per se increased significantly hippocampal PLA2 activity. Conclusion: The present results suggest a functional effect of hippocampal PLA2 on the neurochemistry of memory acquisition and support the hypothesis that reduced PLA2 activity may contribute to memory impairment in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: Abnormalities of membrane phospholipid metabolism have been described in Alzheimer's disease (AD). We investigated, with the aid of 31P magnetic resonance spectroscopy, the in vivo intracerebral availability of phosphomonoesters (PME) and phosphodiesters (PDE) in patients with AD. Methods: Eighteen outpatients with mild or moderate probable AD and 16 nondemented elderly volunteers were assessed with the Cambridge Examination for Mental Disorders of the Elderly (CAMDEX) and its cognitive subscale of the CAMDEX schedule (CAMCOG). Scans were performed on a 1.5 T magnetic resonance imager addressing a 40-cm³ voxel in the left prefrontal cortex. Main outcome measures were mean relative peak areas of PME and PDE, which provide an estimate of membrane phospholipid metabolism. Results: PME resonance and the PME/PDE ratio were increased in AD patients as compared to controls (p<0.05). PME was negatively correlated with global cognitive performance as shown by the Mini-Mental State Examination (rs=-0.36, p=0.05) and CAMCOG scores (rs=-0.49, p=0.007), as well as with discrete neuropsychological functions, namely, memory (rs=-0.53, p=0.004), visual perception (rs=-0.54, p=0.003), orientation (rs=-0.36, p=0.05), and abstract thinking (rs=-0.48, p=0.01). Conclusions: We provide evidence of reduced membrane phospholipid breakdown in the prefrontal cortex of mild and moderately demented AD patients. These abnormalities correlate with neuropsychological deficits that are characteristic of AD. [ABSTRACT FROM AUTHOR]