Aggregation of β‐Amyloid Peptide Is Promoted by Membrane Phospholipid Metabolites Elevated in Alzheimer's Disease Brain

Klunk, William E.; Xu, Changhao; McClure, Richard J.; Panchalingam, K.; Stanley, Jeff; Pettegrew, Jay W.

doi:10.1046/j.1471-4159.1997.69010266.x

Cited by 29 publications

(9 citation statements)

References 43 publications

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“…The NMR PDE findings have been confirmed by classical neurochemical analyses of AD brain which also demonstrate elevated levels of GPC (14). Previous light scattering studies demonstrated that GPC enhances Ab aggregation (15). The present study examines by fluorescence spectroscopy the interaction of Ab and GPC with the intact erythrocyte membrane to determine a possible pathophysiological role for elevated levels of GPC in AD.…”

Section: Introductionsupporting

confidence: 71%

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Interactions of A?(1?40) with Glycerophosphocholine and Intact Erythrocyte Membranes: Fluorescence and Circular Dichroism Studies

2004

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Deposition of amyloid beta peptide in human brain in the form of senile plaques is a neuropathological hallmark of Alzheimer's disease (AD). Levels of a phospholipid breakdown product, glycerophosphocholine (GPC), also increase in AD brain. The effect of GPC on amyloid beta(1-40) peptide (Abeta) aggregation in PBS buffer was investigated by circular dichroism and fluoresence spectroscopy; interactions of Abeta and GPC with the intact erythrocyte membrane was examined by fluoresence spectroscopy. Fluorescamine labeled Abeta studies indicate GPC enhances Abeta aggregation. CD spectroscopy reveals that Abeta in the presence of GPC adopts 14% more beta-sheet structure than does Abeta alone. Fluorescamine anisotropy measurements show that GPC and Abeta interact in the phospholipid head-group region of the erythrocyte membrane. In summary, both soluble Abeta and GPC insert into the phospholipid head-group region of the membrane where they interact leading to beta-sheet formation in soluble Abeta which enhances Abeta aggregation.

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Section: Introductionsupporting

confidence: 71%

“…In our earlier work, aggregation of Ab was measured by a light scattering method (absorption at 400 nm) (15). This methodology is based on measuring the turbidity due to insoluble, aggregated Ab (26).…”

Section: Discussionmentioning

confidence: 99%

Interactions of A?(1?40) with Glycerophosphocholine and Intact Erythrocyte Membranes: Fluorescence and Circular Dichroism Studies

2004

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“…The intensities of these biomarkers do not show significant changes over time in the TERT transgenic group. Interestingly, some of the metabolites identified here (ie, sphingomyelin, glycerophosphoethanolamines) have been previously linked to neurodegenerative disorders and various aspects of aging and disease (Klunk et al 1997; Cutler & Mattson 2001). …”

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confidence: 91%

A metabolic signature predicts biological age in mice

et al. 2012

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Our understanding of the mechanisms by which aging is produced is still very limited. Here, we have determined the sera metabolite profile of 117 wild-type mice of different genetic backgrounds ranging from 8-129 weeks of age. This has allowed us to define a robust metabolomic signature and a derived metabolomic score that reliably/accurately predicts the age of wild-type mice. In the case of telomerase-deficient mice, which have a shortened lifespan, their metabolomic score predicts older ages than expected. Conversely, in the case of mice that over-express telomerase, their metabolic score corresponded to younger ages than expected. Importantly, telomerase reactivation late in life by using a TERT based gene therapy recently described by us, significantly reverted the metabolic profile of old mice to that of younger mice, further confirming an anti-aging role for telomerase. Thus, the metabolomic signature associated to natural mouse aging accurately predicts aging produced by telomere shortening, suggesting that natural mouse aging is in part produced by presence of short telomeres. These results indicate that the metabolomic signature is associated to the biological age rather than to the chronological age. This constitutes one of the first aging-associated metabolomic signatures in a mammalian organism.

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“…An age-related change has been detected in asymmetric membrane cholesterol distribution [82]. Similarly, a progressive increase in phospholipid metabolite formation has been observed during aging, which is accelerated in AD [83]. Elevation of membrane phospholipid metabolites may play a role in the deposition of Ai, as some of these metabolites are known to increase the aggregation of Ai.…”

Section: Control Of Membrane Properties By Cholesterolmentioning

confidence: 95%

Molecular basis of Alzheimer's disease

Drouet

Pinçon‐Raymond

Chambaz

et al. 2000

Cellular and Molecular Life Sciences (CMLS)

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Despite an exponential production of data, Alzheimer's disease (AD) remains an enigma. Unresolved questions persist in the face of the heterogeneity of this neuropathology. Recent progress in understanding mechanisms for AD results from the study of amyloid precursor protein (APP) metabolism and the involvement of senile plaque-associated proteins. In addition to the amyloid cascade hypothesis, alternative schemes emerge, in which the amyloid peptide is not the primary effector of the disease. Perturbations of vesicular trafficking, the cytoskeletal network, and membrane cholesterol distribution could be central events. Furthermore, since the physiological role of APP, presenilins, and apolipoprotein E in the central nervous system are not completely understood, their involvement in AD etiology remains speculative. New actors have to be found to try to explain sporadic cases and non-elucidated familial cases.

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Aggregation of β‐Amyloid Peptide Is Promoted by Membrane Phospholipid Metabolites Elevated in Alzheimer's Disease Brain

Cited by 29 publications

References 43 publications

Interactions of A?(1?40) with Glycerophosphocholine and Intact Erythrocyte Membranes: Fluorescence and Circular Dichroism Studies

Interactions of A?(1?40) with Glycerophosphocholine and Intact Erythrocyte Membranes: Fluorescence and Circular Dichroism Studies

A metabolic signature predicts biological age in mice

Molecular basis of Alzheimer's disease

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