Evidence for a membrane defect in Alzheimer disease brain.

Abstract

To determine whether neurodegeneration in Alzheimer disease brain is associated with degradation of structural cell membrane molecules, we measured tissue levels of the major membrane phospholipids and their metabolites in three cortical areas from postmortem brains of Alzheimer disease patients and matched controls. Among phospholipids, there was a significant (P < 0.05) decrease in phosphatidylcholine and phosphatidylethanolamine. There were significant (P < 0.05) decreases in the initial phospholipid precursors choline and ethanolamine and increases in the phospholipid deacylation product glycerophosphocholine. The ratios of glycerophosphocholine to choline and glycerophosphoethanolamine to ethanolamine were significantly increased in all examined Alzheimer disease brain regions. The activity of the glycerophosphocholine-degrading enzyme glycerophosphocholine cholinephosphodiesterase was normal in Alzheimer disease brain. There was a near stoichiometric relationship between the decrease in phospholipids and the increase of phospholipid catabolites. These data are consistent with increased membrane phospholipid degradation in Alzheimer disease brain. Similar phospholipid abnormalities were not detected in brains of patients with Huntington disease, Parkinson disease, or Down syndrome. We conclude that the phospholipid abnormalities described here are not an epiphenomenon of neurodegeneration and that they may be specific for the pathomechanism of Alzheimer disease.Brain lesions characteristic of Alzheimer disease (AD) include amyloid deposition, the formation of neurofibrillary tangles, and neuronal degeneration. The etiology and pathophysiology of neuronal death in AD are unknown. Cell membrane lipid abnormalities have been described in AD brain, and it has been hypothesized that these contribute to amyloid deposition (1, 2) and neuronal dysfunction (3). Initial evidence for a biochemical abnormality in the metabolism of phospholipids came from in vitro 31P NMR spectroscopic studies showing that the ratio of glycerophosphocholine (GPC) to glycerophosphoethanolamine (GPE) as well as levels of glycerophosphodiesters and phosphomonoesters were increased in AD brain (4-6). Quantitative HPLC analysis has demonstrated that the increase in glycerophosphodiesters was due to accumulation of the phospholipid catabolites GPC and GPE (7, 8). The biochemical mechanisms accounting for the increase of phospholipid catabolites are unknown. To investigate the abnormalities in the phospholipid metabolic pathways, we examined levels of the parent phospholipids, their precursors, and their catabolites (see Fig. 1) in three cortical brain areas obtained at autopsy from AD patients and matched controls. To rule out the possibility that the elevation in GPC reflects a slowing in its degradation,

Brain Incorporation of [11C]Arachidonic Acid in Young Healthy Humans Measured with Positron Emission Tomography

“…The AA method could be applied to older healthy subjects (McGahon et al, 1997;Giovacchini et al, 2002), and disorders such as Alzheimer disease and schizophrenia (Farooqui et al, 1988;Nitsch et al, 1992;McGahon et al, 1997;Smalheiser and Swanson, 1998;Hudson et al, 1999;Patrick et al, 2000). In these conditions, AA and PLA 2 abnormalities have been reported in cortical areas related to physiologic and pathologic changes.…”

“…Alterations in AA-containing phospholipids and/or PLA 2 activity have been reported in normal aging and neuropsychiatric disorders (Farooqui et al, 1988;Nitsch et al, 1992;McGahon et al, 1997;Smalheiser and Swanson, 1998;Hudson et al, 1999;Patrick et al, 2000). Studies in rats with a unilateral lesion of the nucleus basalis magnocellularis or of the substantia nigra, animal models of Alzheimer and Parkinson disease, respectively, have also demonstrated alterations in PLA 2 -mediated cholinergic and dopaminergic signaling Hayakawa et al, 1998).…”

Acetyl-L-carnitine physical-chemical, metabolic, and therapeutic properties: relevance for its mode of action in Alzheimer's disease and geriatric depression

“…There also is solid evidence for a fundamental alteration in membrane phospholipid composition and metabolism in AD. [111][112][113][114][115][116][117][118][119] Of considerable importance is the observation that the membrane molecular changes actually precede cognitive decline. 120 In addition, there is in vivo evidence that ALCAR can reverse these membrane molecular and metabolic changes in some AD subjects.…”

Region-Specific and Calcium-Dependent Increase in Dialysate Choline Levels by NMDA

“…Significant reductions in phosphatidylcholine (PtdCho) levels have been reported in certain neurodegenerative diseases (Nitsch et al, 1992), but the ability of excitotoxic mechanisms to modulate PtdCho metabolism has not been demonstrated.…”