Oligomeric amyloid-β peptide disrupts phosphatidylinositol-4,5-bisphosphate metabolism

Berman, Diego E.; Dall’Armi, Claudia; Voronov, Sergey V.; McIntire, Laura Beth; Zhang, Hong; Moore, Ann Zenobia; Staniszewski, Agniezka; Arancio, Ottavio; Kim, Tae‐Wan; Paolo, Gilbert Di

doi:10.1038/nn.2100

Cited by 173 publications

(191 citation statements)

References 47 publications

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“…Before the use on cell cultures, preparations of A␤ oligomers were analyzed on 10% polyacrylamide gels. Coomassie-blue staining revealed A␤ oligomers to be essentially trimers and tetramers, as previously described (Berman et al, 2008;Youssef et al, 2008; Supplementary Fig. 1).…”

Section: Methodsmentioning

confidence: 60%

“…In this study, we used a more relevant model mimicking the early stages of sporadic AD in which behavioral and synaptic impairments are induced upon acute exposure to small amounts of extracellular A␤ oligomers (Garcia et al, 2010;Youssef et al, 2008). The preparations of synthetic A␤ 42 oligomers used contained predominantly trimers and tetramers similar to those prepared from synthetic batches or produced in recombinant cell systems (Berman et al, 2008; Supplementary Fig. 1).…”

Section: Discussionmentioning

confidence: 99%

“…Finally, many studies identified intracellular mediators of the A␤ peptide neurotoxic effects. These intracellular targets include membrane-phospholipid remodeling enzymes such as synaptojanin and phospholipase D (Berman et al, 2008;Oliveira et al, 2010) or signaling proteins such as fyn kinase, glycogen synthase kinase-3␤, cyclin-dependent kinase-5 (Crews and Masliah, 2010). Some inhibitors of these putative therapeutic targets have been proposed because of their potential specificity.…”

Section: Discussionmentioning

confidence: 99%

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Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

Desbène

Malaplate-Armand

Youssef

et al. 2012

Neurobiology of Aging

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Soluble beta-amyloid (A␤) oligomers are considered to putatively play a critical role in the early synapse loss and cognitive impairment observed in Alzheimer's disease. We previously demonstrated that A␤ oligomers activate cytosolic phospholipase A 2 (cPLA 2 ), which specifically releases arachidonic acid from membrane phospholipids. We here observed that cPLA 2 gene inactivation prevented the alterations of cognitive abilities and the reduction of hippocampal synaptic markers levels noticed upon a single intracerebroventricular injection of A␤ oligomers in wild type mice. We further demonstrated that the A␤ oligomer-induced sphingomyelinase activation was suppressed and that phosphorylation of Akt/protein kinase B (PKB) was preserved in neuronal cells isolated from cPLA 2 Ϫ/Ϫ mice. Interestingly, expression of the A␤ precursor protein (APP) was reduced in hippocampus homogenates and neuronal cells from cPLA 2 Ϫ/Ϫ mice, but the relationship with the resistance of these mice to the A␤ oligomer toxicity requires further investigation. These results therefore show that cPLA 2 plays a key role in the A␤ oligomer-associated neurodegeneration, and as such represents a potential therapeutic target for the treatment of Alzheimer's disease.

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Section: Methodsmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

Desbène

Malaplate-Armand

Youssef

et al. 2012

Neurobiology of Aging

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“…Although the data tend to rule out a direct role for PIP in membrane merger (FFM), they identify an important link with efficiency (PFM), particularly with regard to fusion rate. The involvement of key phosphoinositide, PE, and CHOL metabolism reactions in different disease states emphasizes the importance of this research [3,7,69]. Using selective pharmacological interventions at specific steps of metabolic pathways, this new ex vivo approach enables effective and meaningful molecular alterations that aid further dissection of fundamental priming, docking, and membrane fusion mechanisms.…”

Section: Discussionmentioning

confidence: 99%

A new approach to the molecular analysis of docking, priming, and regulated membrane fusion

Rogasevskaia

Coorssen

2011

J Chem Biol

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Studies using isolated sea urchin cortical vesicles have proven invaluable in dissecting mechanisms of Ca 2+ -triggered membrane fusion. However, only acute molecular manipulations are possible in vitro. Here, using selective pharmacological manipulations of sea urchin eggs ex vivo, we test the hypothesis that specific lipidic components of the membrane matrix selectively affect defined late stages of exocytosis, particularly the Ca 2+ -triggered steps of fast membrane fusion. Egg treatments with cholesterol-lowering drugs resulted in the inhibition of vesicle fusion. Exogenous cholesterol recovered fusion extent and efficiency in cholesterol-depleted membranes; α-tocopherol, a structurally dissimilar curvature analogue, selectively restored fusion extent. Inhibition of phospholipase C reduced vesicle phosphatidylethanolamine and suppressed both the extent and kinetics of fusion. Although phosphatidylinositol-3-kinase inhibition altered levels of polyphosphoinositide species and reduced all fusion parameters, sequestering polyphosphoinositides selectively inhibited fusion kinetics. Thus, cholesterol and phosphatidylethanolamine play direct roles in the fusion pathway, contributing negative curvature. Cholesterol also organizes the physiological fusion site, defining fusion efficiency. A selective influence of phosphatidylethanolamine on fusion kinetics sheds light on the local microdomain structure at the site of docking/fusion. Polyphosphoinositides have modulatory upstream roles in priming: alterations in specific polyphosphoinositides likely represent the terminal priming steps defining fully docked, release-ready vesicles. Thus, this pharmacological approach has the potential to be a robust high-throughput platform to identify molecular components of the physiological fusion machine critical to docking, priming, and triggered fusion.

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“…Levels of phosphoinositides and other anionic phospholipids were measured and quantified in brain extracts by using HPLC with suppressed conductivity detection (19)(20)(21). A representative chromatogram of a deacylated lipid extract from mouse brain is shown in Fig.…”

Section: Synaptojanin 1 Overexpression In the Brain Of Ds Mouse Modelsmentioning

confidence: 99%

Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down's syndrome

Voronov

Frère²,

Giovedì³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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152

139

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Phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2] is a signaling phospholipid implicated in a wide variety of cellular functions. At synapses, where normal PtdIns(4,5)P 2 balance is required for proper neurotransmission, the phosphoinositide phosphatase synaptojanin 1 is a key regulator of its metabolism. The underlying gene, SYNJ1, maps to human chromosome 21 and is thus a candidate for involvement in Down's syndrome (DS), a complex disorder resulting from the overexpression of trisomic genes. Here, we show that PtdIns(4,5)P2 metabolism is altered in the brain of Ts65Dn mice, the most commonly used model of DS. This defect is rescued by restoring Synj1 to disomy in Ts65Dn mice and is recapitulated in transgenic mice overexpressing Synj1 from BAC constructs. These transgenic mice also exhibit deficits in performance of the Morris water maze task, suggesting that PtdIns(4,5)P 2 dyshomeostasis caused by gene dosage imbalance for Synj1 may contribute to brain dysfunction and cognitive disabilities in DS.Alzheimer's disease ͉ inositol 5-phosphatase ͉ phosphatidylinositol-4,5-bisphosphate ͉ phosphatidylinositol phosphate kinase ͉ synapse

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Oligomeric amyloid-β peptide disrupts phosphatidylinositol-4,5-bisphosphate metabolism

Cited by 173 publications

References 47 publications

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

A new approach to the molecular analysis of docking, priming, and regulated membrane fusion

Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down's syndrome

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