“Autocannibalism” of choline-containing membrane phospholipids in the pathogenesis of Alzheimer's disease—A hypothesis

Wurtman, Richard J.; Blusztajn, Jan Krzysztof; Maire, J. C.

doi:10.1016/0197-0186(85)90127-5

Cited by 91 publications

(32 citation statements)

References 13 publications

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“…Cholinergic neurons may be selectively vulnerable in Alzheimer's disease because they require choline for the synthesis of both the neurotransmitter acetylcholine and the membrane structural component phosphatidylcholine. The autocannibalism hypothesis suggests that cholinergic neurons in Alzheimer's disease compensate for a deficiency of free choline for acetylcholine synthesis by degradation of membrane phosphatidylcholine (2). This hypothesis is supported by studies of postmortem brain tissue from Alzheimer's disease patients that show higher than normal cellular levels of the phospholipid catabolic intermediate glycerophosphocholine (3,4).…”

supporting

confidence: 63%

Brain proton magnetic resonance spectroscopy (1H-MRS) in Alzheimer's disease: changes after treatment with xanomeline, an M1 selective cholinergic agonist

Satlin

Bodick²,

Offen³

et al. 1997

AJP

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supporting

confidence: 63%

Brain proton magnetic resonance spectroscopy (1H-MRS) in Alzheimer's disease: changes after treatment with xanomeline, an M1 selective cholinergic agonist

Satlin

Bodick²,

Offen³

et al. 1997

AJP

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“…Increased levels of phosphocholine and glycerophosphocholine are found (Barany et al, 1985;Pettegrew et al, 1987Pettegrew et al, , 1988a. Although by contrast the levels of phosphoethanolamine and ethanolamine are reported to be reduced in AD brain (Ellison et al, 1987;Perry et al, 1987), the findings on choline esters are thought to support the hypothesis of defective biosynthesis of membrane phospholipids, perhaps a generalized defect preceding the degenerative formation of senile plaques that, in turn, may be associated with degradation of phospholipids (Wurtman et al, 1985;Blusztajn, et al, 1986;Pettegrew et al, 1988b). In the present study, a reduction in PC concentration was found in AD frontal cortex, which is consistent with the above hypothesis.…”

Section: Major Lipid Classessupporting

confidence: 52%

Lipid abnormalities in the brain in adult Down’s syndrome and Alzheimer’s disease

Brooksbank

Martínez

1989

Molecular and Chemical Neuropathology

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Quantitative analysis by HPTLC of the major lipid classes and dolichol, and of fatty acyl groups of separated phosphoglycerides by capillary GLC, has been carried out on the gray matter of frontal cerebral cortex of brains from six Down's syndrome (DS) and six Alzheimer's disease (AD) adults, and six each of two corresponding sets of age-matched controls; specimens of DS and control cerebellum and corpus callosum were also analyzed. In DS frontal cortex, but not in AD frontal cortex, compared to their respective controls there was a decrease in the fraction of phosphatidylethanolamine (PE) and an increase in the fractions of sphingomyelin (SPM) and phosphatidylserine (PS). Abnormalities were not found in the proportions of major lipid classes in DS cerebellum or corpus callosum. The concentration of dolichol was elevated for age in the frontal cortex of DS and of AD. In the phosphoglycerides of DS frontal cortex, the fatty acyl composition showed small, but statistically significant, differences from those of age-matched controls, and some slight abnormalities were also detected in DS corpus callosum. The alterations in DS frontal cortex included decreases in (n-6) and increases in (n-3) groups in choline and ethanolamine phosphoglycerides (CPG and EPG), as had previously been found in EPG and serine phosphoglyceride (SPG) of the DS fetal brain. In DS frontal cortex, the proportion of 22:4(n-6) groups was decreased in SPG, and in inositol phosphoglyceride (IPG) 18:1(n-9) was increased. There were also small but significant alterations in DS frontal cortex in the fractions of shorter chain groups in CPG. In marked contrast, most of the fatty acyl abnormalities seen in DS were absent in the AD frontal cortex. It is therefore suggested that some abnormalities in the composition of cerebral membranes present prenatally in DS may persist into adulthood, and are not directly related to AD-type pathology.

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“…It has also been hypothesized that the elevation of the Cho peak is the consequence of membrane phosphatidylcholine catabolism to provide free choline for the chronically deficient acetylcholine production in AD. 32,33 Elevated Cho/Cr levels in patients with dementia with Lewy bodies characterized by a profound cholinergic deficit further support the hypothesis that elevation in Cho/Cr may be associated with cholinergic dysfunction. 34 Cho/Cr levels decrease with cholinergic agonist treatment in AD, suggesting that downregulation of choline acetyltransferase activity may be responsible for the elevation of Cho.…”

Section: C-pittsburgh Compound B (Pib) Retention Ratiomentioning

confidence: 51%

Magnetic resonance spectroscopy, β-amyloid load, and cognition in a population-based sample of cognitively normal older adults

et al. 2011

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Objective: To determine the relationship between proton magnetic resonance spectroscopy ( 1 H MRS) metabolites and ␤-amyloid (A␤) load and the effects of A␤ load on the association between 1 H MRS metabolites and cognitive function in cognitively normal older adults. Methods:We studied 311 cognitively normal older adults who participated in the population- GLOSSARY A␤ ϭ ␤-amyloid; AD ϭ Alzheimer disease; AVLT ϭ Auditory Verbal Learning Test; Cho ϭ choline; Cr ϭ creatine; GM ϭ gray matter; 1 H MRS ϭ proton magnetic resonance spectroscopy; MCI ϭ mild cognitive impairment; MCSA ϭ Mayo Clinic Study of Aging; mI ϭ myoinositol; MPRAGE ϭ magnetization-prepared rapid gradient echo; NAA ϭ N-acetylaspartate; PiB ϭ 11 CPittsburgh compound B; SV ϭ single voxel; WAIS-R ϭ Wechsler Adult Intelligence Scale-Revised.Biomarkers of preclinical Alzheimer disease (AD) pathology are critical for identifying at-risk individuals for preventive clinical trials.1 A potential imaging marker for early detection of AD pathology is proton magnetic resonance spectroscopy ( 1 H MRS), which allows noninvasive assessment of brain biochemistry. 1 H MRS metabolite abnormalities, characterized by increased levels of the glial metabolite myoinositol (mI) and decreased levels of the neuronal metabolite N-acetylaspartate (NAA), are associated with the severity of AD pathology.2 Both decreased NAA and increased mI levels have been detected in individuals who have a higher risk for developing AD, such as patients with amnestic mild cognitive impairment (MCI), 3,4 and in presymptomatic carriers of familial AD mutations.5 Furthermore, an elevation in the choline (Cho)/creatine (Cr) ratio predicted future cognitive decline in cognitively normal older adults.

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“Autocannibalism” of choline-containing membrane phospholipids in the pathogenesis of Alzheimer's disease—A hypothesis

Cited by 91 publications

References 13 publications

Brain proton magnetic resonance spectroscopy (1H-MRS) in Alzheimer's disease: changes after treatment with xanomeline, an M1 selective cholinergic agonist

Brain proton magnetic resonance spectroscopy (1H-MRS) in Alzheimer's disease: changes after treatment with xanomeline, an M1 selective cholinergic agonist

Lipid abnormalities in the brain in adult Down’s syndrome and Alzheimer’s disease

Magnetic resonance spectroscopy, β-amyloid load, and cognition in a population-based sample of cognitively normal older adults

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