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Reduced phospholipase A2 (PLA2) activity and increased phosphorylation of glycogen synthase kinase 3B (GSK3B) participate in the production of beta-amyloid plaques and of neurofibrillary tangles, which are two neuropathological hallmarks of Alzheimer's disease (AD). Experimental evidences suggest a neuroprotective effect of the cholinesterase inhibitor donepezil in the treatment the disease. The aims of the present study were to evaluate in AD patients the effects of treatment with donepezil on PLA2 activity and GSK3B level. Thirty patients with AD were treated during 6 months with 10 mg daily of donepezil. Radio-enzymatic assays were used to measure PLA2 activity and Elisa assays for GSK3B level, both in platelets. Before treatment and after 3 and 6 months on donepezil, AD patients underwent a cognitive assessment and platelet samples were collected. Values were compared to a healthy control group of 42 sex- and age-matched elderly individuals. Before treatment, iPLA2 activity was lower in patients with AD as compared to controls ( p < 0.001). At baseline, no differences were found in GSK3B level between both groups. After 3 and 6 months of treatment, we found a significant increase in iPLA2 activity ( p = 0.015 and p < 0.001, respectively). iPLA2 increment was related to the cognitive improvement during treatment ( p = 0.037). After 6 months, we found an increase in phosphorylated GSK3B ( p = 0.02). The present findings suggest two possible mechanisms by which donepezil delays the progression of AD. The increment of iPLA2 activity may reduce the production of beta-amyloid plaques, whereas the phosphorylation of GSK3B inactivates the enzyme, reducing thus the phosphorylation of tau protein. [ABSTRACT FROM AUTHOR]

Background: Previous studies have reported an association between executive dysfunction and the ability to perform activities of daily living (ADL)s among older adults. This study aims to examine the association between executive functions and functional status in a cross-section of older adults with varying degrees of cognitive impairment. Methods: 89 individuals (mean age 73.8 years) were recruited at a memory clinic in São Paulo, Brazil. Subjects underwent evaluation, and were allocated into three diagnostic groups according to cognitive status: normal controls (NC, n = 32), mild cognitive impairment (MCI, n = 31) and mild Alzheimer's disease (AD, n=26). Executive functions were assessed with the 25-item Executive Interview (EXIT25), and functional status was measured with the Direct Assessment of Functional Status test (DAFS-R). Results: Significantly different total DAFS-R scores were observed across the three diagnostic groups. Patients with AD performed significantly worse in EXIT25 compared with subjects without dementia, and no significant differences were detected between NC and MCI patients. We found a robust negative correlation between the DAFS-R and the EXIT25 scores (r =-0.872, p <0.001). Linear regression analyses suggested a significant influence of the EXIT-25 and the CAMCOG on the DAFS-R scores. Conclusion: Executive dysfunction and decline in general measures of cognitive functioning are associated with a lower ability to undertake instrumental ADLs. MCI patients showed worse functional status than NC subjects. MCI patients may show subtle changes in functional status that may only be captured by objective measures of ADLs. [ABSTRACT FROM AUTHOR]

Phospholipase A2 (PLA2) is a key enzyme in cerebral phospholipid metabolism. Preliminary post-mortem studies have shown that PLA2 activity is decreased in frontal and parietal areas of the AD brain, which is in accordance with recent 31P-Magnetic Resonance Spectroscopy evidence of reduced phospholipid turnover in the pre-frontal cortex of moderately demented AD patients. Such abnormality may also be observed in peripheral cells, and reduced PLA2 activity in platelet membranes of AD patients, and correlates with the severity of dementia. In rat hippocampal slices, PLA2 has been implicated in mechanisms of synaptic plasticity. In adult rats, the stereotaxic injection of PLA2 inhibitors in the CA1 area of hippocampus impaired, in a dose-dependent manner, the formation of short- and long-term memory. Additionally, such inhibition resulted in a reduction of the fluidity of hippocampal membranes. In primary cultures of cortical and hippocampal neurons, the inhibition of PLA2 precluded neurite outgrowth, and the sustained inhibition of the enzyme in mature cultures lead to loss of viability. Taken together, these findings reinforce the involvement of PLA2 enzymes in neurodevelopment and neurodegeneration processes, and further suggest that reduced PLA2 activity, probably reducing membrane phospholipids breakdown, may contribute to the memory impairment in AD. [ABSTRACT FROM AUTHOR]

Summary. Phospholipase A2 (PLA2) controls the metabolism of phospholipids in cell membranes. In the brain, PLA2 influences the processing of the amyloid precursor protein (APP) and thus the production of the amyloid-beta peptides (Aβ), which are the major components of the senile plaques in Alzheimer’s disease (AD). Reduced PLA2 activity has been reported in brain and in platelets of AD patients. In the present study we investigated PLA2 activity in platelets from 21 AD patients as compared to 17 healthy elderly controls and 11 individuals with mild cognitive impairment (MCI). Subjects were cognitively assessed by the Mini-Mental State Examination (MMSE) and the CAMDEX schedule. Platelet PLA2 activity was determined by radio-enzymatic assay, which mainly detected a calcium-independent form of the enzyme present also in the brain (iPLA2). PLA2 activity was significantly lower in AD than in controls (p < 0.001). Mean PLA2 activity in MCI individuals was between the values of AD patients and controls, with a subgroup showing PLA as low as the lowest AD patients, but the differences from MCI were not significant from AD and control groups. Lower PLA2 activity was significantly correlated with a worse cognitive performance both at the MMSE (p = 0.001) and the cognitive sub-scale of the CAMDEX inventory (p = 0.002). Our data replicate previous findings of reduced platelet PLA2 activity in AD. Both reduced PLA2 activity and the correlation with impaired cognition were also reported in brain tissue of AD patients, suggesting thus that the present determinations in platelets may be related to a reduction in the brain. In the brain the inhibition of PLA2 inhibits the physiological secretion of the APP, a mechanism that increases Aβ formation. Further longitudinal studies should investigate whether those MCI individuals with the lowest PLA2 values in platelets would be at a higher risk to develop AD during a longitudinal follow up. [ABSTRACT FROM AUTHOR]

Summary. Muscarinic agonists alter the metabolism of amyloid precursor protein, leading to an increase in α-secretase cleavage and a decreased production of amyloidogenic peptides; suggesting that these compounds might modify the Alzheimer's disease process. A second therapeutic target in AD is the accumulation of stably phosphorylated tau into neurofibrillary tangles; an early event correlating with cognitive impairment. Glycogen synthase kinase-3 (GSK-3β) phosphorylates tau and is inhibited via protein kinase C (PKC). As certain muscarinic receptors are linked to PKC, we examined the effect of a range of agonists on GSK-3β phosphorylation of tau. In neurons a non-specific muscarinic agonist, carbachol, reduced tau phosphorylation. In non-neuronal cells expressing the m1 receptor a range of m1 agonists reduced transiently-expressed tau phosphorylation and altered its microtubule-binding properties. These findings link the two pathological process of AD – APP metabolism and tau phosphorylation – and suggest that muscarinic and other cholinergic compounds might have disease-modifying properties. [ABSTRACT FROM AUTHOR]

A response by P. V. Nunes and colleagues to a letter to the editor about their article "Lithium and Risk for Alzheimer's Disease in Elderly Patients With Bipolar Disorder" in a previous issue is presented.