Isoprenoids and tau pathology in sporadic Alzheimer's disease

Pelleïeux, Sandra; Picard, Cynthia; Lamarre-Théroux, Louise; Dea, Doris; Leduc, Valérie; Tsantrizos, Youla S.; Poirier, Judes

doi:10.1016/j.neurobiolaging.2018.01.012

Cited by 29 publications

(19 citation statements)

References 51 publications

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“…High cortical levels of FPP and GGPP significantly correlate with tau phosphorylation, NFT density and early-onset AD. hFPPS and hGGPPS mRNA expression in the cortex positively correlate with levels of HMG-CoA reductase in AD individuals but not with levels of tissues cholesterol [257]. In an AD mouse model, atorvastatin exerts anti-inflammatory effects by reducing FPP [258].…”

Section: Statinsmentioning

confidence: 92%

Lipids and Alzheimer’s Disease

Kao

et al. 2020

IJMS

325

263

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Lipids, as the basic component of cell membranes, play an important role in human health as well as brain function. The brain is highly enriched in lipids, and disruption of lipid homeostasis is related to neurologic disorders as well as neurodegenerative diseases such as Alzheimer’s disease (AD). Aging is associated with changes in lipid composition. Alterations of fatty acids at the level of lipid rafts and cerebral lipid peroxidation were found in the early stage of AD. Genetic and environmental factors such as apolipoprotein and lipid transporter carrying status and dietary lipid content are associated with AD. Insight into the connection between lipids and AD is crucial to unraveling the metabolic aspects of this puzzling disease. Recent advances in lipid analytical methodology have led us to gain an in-depth understanding on lipids. As a result, lipidomics have becoming a hot topic of investigation in AD, in order to find biomarkers for disease prediction, diagnosis, and prevention, with the ultimate goal of discovering novel therapeutics.

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Section: Statinsmentioning

confidence: 92%

Lipids and Alzheimer’s Disease

Kao

et al. 2020

IJMS

325

263

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“…In addition, the dysregulation of this kinase both in in vitro and in vivo AD models affects Aβ and Tau metabolism [ 112 ]. In AD, increased neuronal isoprenoid levels induce Cdc42 prenylation, promoting Tau phosphorylation and the consequent NFT formation [ 115 ]. Cdc42 activates GSK3β, which is responsible for Tau phosphorylation.…”

Section: Small Gtpases Of the Rho Familymentioning

confidence: 99%

Small GTPases of the Ras and Rho Families Switch on/off Signaling Pathways in Neurodegenerative Diseases

Sastre

Montoro

Gálvez‐Martín

et al. 2020

IJMS

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Small guanosine triphosphatases (GTPases) of the Ras superfamily are key regulators of many key cellular events such as proliferation, differentiation, cell cycle regulation, migration, or apoptosis. To control these biological responses, GTPases activity is regulated by guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and in some small GTPases also guanine nucleotide dissociation inhibitors (GDIs). Moreover, small GTPases transduce signals by their downstream effector molecules. Many studies demonstrate that small GTPases of the Ras family are involved in neurodegeneration processes. Here, in this review, we focus on the signaling pathways controlled by these small protein superfamilies that culminate in neurodegenerative pathologies, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Specifically, we concentrate on the two most studied families of the Ras superfamily: the Ras and Rho families. We summarize the latest findings of small GTPases of the Ras and Rho families in neurodegeneration in order to highlight these small proteins as potential therapeutic targets capable of slowing down different neurodegenerative diseases.

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“…Accordingly, the aberrant protein prenylation has a greater effect on AD than cholesterol itself [62]. Most recent experiments bring to light cholesterol metabolism in pathology of sporadic AD (late-onset Alzheimer’s disease, LOAD), as well as genes related to sterol metabolism [69,70]. It is clear from these reports that phosphorylated Tau (p-Tau) protein level and NFT density in the frontal cortex resulted from increased FPP and GGPP synthesis, and that sterol regulatory element binding transcription factor 2 ( SREBF2 ) gene expression levels in LOAD frontal cortices were inversely related to age of death.…”

Section: Discussionmentioning

confidence: 99%

Preliminary Study on Clusterin Protein (sCLU) Expression in PC-12 Cells Overexpressing Wild-Type and Mutated (Swedish) AβPP genes Affected by Non-Steroid Isoprenoids and Water-Soluble Cholesterol

Pająk

Kania

Gołaszewska

et al. 2019

IJMS

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In this study we attempted to verify the hypothesis that the mevalonate pathway affects amyloid beta precursor protein (AβPP) processing and regulates clusterin protein levels. AβPP expression was monitored by green fluorescence (FL) and Western blot (WB). WB showed soluble amyloid protein precursor alpha (sAβPPα) presence in AβPP-wt cells and Aβ expression in AβPP-sw cells. Nerve growth factor (NGF)-differentiated rat neuronal pheochromocytoma PC-12 cells were untreated/treated with statins alone or together with non-sterol isoprenoids. Co-treatment with mevalonate, dolichol, ubiquinol, farnesol, geranylgeraniol, or water-soluble cholesterol demonstrated statin-dependent neurotoxicity resulted from the attenuated activity of mevalonate pathway rather than lower cholesterol level. Atorvastatin (50 μM) or simvastatin (50 μM) as well as cholesterol chelator methyl-β-cyclodextrin (0.2 mM) diminished cell viability (p < 0.05) and clusterin levels. Interestingly, co-treatment with mevalonate, dolichol, ubiquinol, farnesol, geranylgeraniol, or water-soluble cholesterol stimulated (p < 0.05) clusterin expression. Effects of non-sterol isoprenoids, but not water soluble cholesterol (Chol-PEG), were the most significant in mock-transfected cells. Geranylgeraniol (GGOH) overcame atorvastatin (ATR)-dependent cytotoxicity. This effect does not seem to be dependent on clusterin, as its level became lower after GGOH. The novelty of these findings is that they show that the mevalonate (MEV) pathway rather than cholesterol itself plays an important role in clusterin expression levels. In mock-transfected, rather than in AβPP-overexpressing cells, GGOH/farnesol (FOH) exerted a protective effect. Thus, protein prenylation with GGOH/FOH might play substantial role in neuronal cell survival.

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Isoprenoids and tau pathology in sporadic Alzheimer's disease

Cited by 29 publications

References 51 publications

Lipids and Alzheimer’s Disease

Lipids and Alzheimer’s Disease

Small GTPases of the Ras and Rho Families Switch on/off Signaling Pathways in Neurodegenerative Diseases

Preliminary Study on Clusterin Protein (sCLU) Expression in PC-12 Cells Overexpressing Wild-Type and Mutated (Swedish) AβPP genes Affected by Non-Steroid Isoprenoids and Water-Soluble Cholesterol

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