Lipids and Alzheimer's disease

Garner, Brett

doi:10.1016/j.bbalip.2010.06.003

Cited by 13 publications

(10 citation statements)

References 30 publications

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“…Amyloidogenic processing of the amyloid precursor protein in early endosomes of neurons was also observed in Niemann-Pick disease, type C (Jin et al, 2004). The presence of certain lipids (Garner, 2010), especially gangliosides (Ariga et al, 2008) appears to be required for the formation of amyloid fibrils in Alzheimer disease. The conformational transition of the amyloid ␤-protein from random coiled to a more ordered one that is rich in ␤-sheets is facilitated by binding to gangliosides as the initial step (Ariga et al, 2008;Matsuzaki et al, 2010).…”

Section: Folding Diseasesmentioning

confidence: 91%

A view on sphingolipids and disease

Kolter

2011

Chemistry and Physics of Lipids

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Section: Folding Diseasesmentioning

confidence: 91%

A view on sphingolipids and disease

Kolter

2011

Chemistry and Physics of Lipids

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“…There is accumulating data to suggest that alterations in cerebral lipid homoeostasis may be directly associated with AD (see [48] for a review). Based on the fact that APP is a type I membrane protein that is proteolytically processed to form Aβ in sphingolipid-enriched membrane microdomains, the possibility that modulation of membrane lipid composition could represent a novel means to regulate Aβ production presents a plausible basis for AD therapeutic intervention [9,11,49–52].…”

Section: Discussionmentioning

confidence: 99%

Dissociation of ERK signalling inhibition from the anti-amyloidogenic action of synthetic ceramide analogues

Evin

Hill

et al. 2012

Clinical Science

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Inhibition of GSL (glycosphingolipid) synthesis reduces Aβ (amyloid β-peptide) production in vitro. Previous studies indicate that GCS (glucosylceramide synthase) inhibitors modulate phosphorylation of ERK1/2 (extracellular-signal-regulated kinase 1/2) and that the ERK pathway may regulate some aspects of Aβ production. It is not clear whether there is a causative relationship linking GSL synthesis inhibition, ERK phosphorylation and Aβ production. In the present study, we treated CHO cells (Chinese-hamster ovary cells) and SH-SY5Y neuroblastoma cells, that both constitutively express human wild-type APP (amyloid precursor protein) and process this to produce Aβ, with GSL-modulating agents to explore this relationship. We found that three related ceramide analogue GSL inhibitors, based on the PDMP (D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol) structure, reduced cellular Aβ production and in all cases this was correlated with inhibition of pERK (phosphorylated ERK) formation. Importantly, the L-threo enantiomers of these compounds (that are inferior GSL synthesis inhibitors compared with the D-threo-enantiomers) also reduced ERK phosphorylation to a similar extent without altering Aβ production. Inhibition of ERK activation using either PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one] or U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio] butadiene) had no impact on Aβ production, and knockdown of endogenous GCS using small interfering RNA reduced cellular GSL levels without suppressing Aβ production or pERK formation. Our data suggest that the alteration in pERK levels following treatment with these ceramide analogues is not the principal mechanism involved in the inhibition of Aβ generation and that the ERK signalling pathway does not play a crucial role in processing APP through the amyloidogenic pathway.

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“…AD is the most common cause of dementia [56], the prevalence of which doubles every five years between 65 and 85 years of age [57]. The accumulation of amyloid β (Aβ) in the brain has been considered as the main culprit in the pathogenesis of AD, resulting in synapse disruption and neuronal destruction.…”

Section: Cognitive Impairment – Mechanisms and Risk Factorsmentioning

confidence: 99%

Gene-Activation Mechanisms in the Regression of Atherosclerosis, Elimination of Diabetes Type 2, and Prevention of Dementia

2011

CMM

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Atherosclerotic vascular disease, diabetes mellitus (DM) and dementia are major global health problems. Both endogenous and exogenous factors activate genes functioning in biological processes. This review article focuses on gene-activation mechanisms that regress atherosclerosis, eliminate DM type 2 (DM2), and prevent cognitive decline and dementia. Gene-activating compounds upregulating functions of liver endoplasmic reticulum (ER) and affecting lipid and protein metabolism, increase ER size through membrane synthesis, and produce an antiatherogenic plasma lipoprotein profile. Numerous gene-activators regress atherosclerosis and reduce the occurrence of atherosclerotic disease. The gene-activators increase glucose disposal rate and insulin sensitivity and, by restoring normal glucose and insulin levels, remove metabolic syndrome and DM2. Patients with DM2 show an improvement of plasma lipoprotein profile and glucose tolerance together with increase in liver phospholipid (PL) and cytochrome (CYP) P450. The gene-activating compounds induce hepatic protein and PL synthesis, and upregulate enzymes including CYPs and glucokinase, nuclear receptors, apolipoproteins and ABC (ATP-binding cassette) transporters. They induce reparation of ER structures and eliminate consequences of ER stress. Healthy living habits activate mechanisms that maintain high levels of HDL and apolipoprotein AI, promote health, and prevent cognitive decline and dementia. Agonists of liver X receptor (LXR) reduce amyloid in brain plaques and improve cognitive performance in mouse models of Alzheimer`s disease. The gene activation increases the capacity to withstand cellular stress and to repair cellular damage and increases life span. Life free of major health problems and in good cognitive health promotes well-being and living a long and active life.

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Lipids and Alzheimer's disease

Cited by 13 publications

References 30 publications

A view on sphingolipids and disease

A view on sphingolipids and disease

Dissociation of ERK signalling inhibition from the anti-amyloidogenic action of synthetic ceramide analogues

Gene-Activation Mechanisms in the Regression of Atherosclerosis, Elimination of Diabetes Type 2, and Prevention of Dementia

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