Phospholipid‐Metabolizing Enzymes in Alzheimer's Disease: Increased Lysophospholipid Acyltransferase Activity and Decreased Phospholipase A<sub>2</sub> Activity

Ross, Brian M.; Moszczynska, Anna; Erlich, Jeffrey C; Kish, Stephen J.

doi:10.1046/j.1471-4159.1998.70020786.x

Cited by 121 publications

(89 citation statements)

References 34 publications

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“…Although consistent with the upregulation in cPLA 2 and LPCAT activities observed in AD and in response to A␤ 42 (3,4,9), the specificity of this metabolic disruption was nonetheless surprising . Disruption in the Land's cycle predicts a general increase in PAF metabolism not the hydrolysis of structural lipids with specific carbon chain lengths (Fig.…”

Section: Discussionsupporting

confidence: 53%

“…These metabolites are biologically active in their own right and can be further modified by lysophosphatidylcholine acyltransferases (LPCATs). LPCAT activity also increases in AD (9), notably in the posterior-temporal entorhinal cortex, a region characterized by the earliest tau pathology (2). Transfer of a long-chain acyl group to the sn-2 position by LPCAT1 and LPCAT2 regenerates structural membrane lipids, whereas addition of a small acetyl group produces a family of powerful lipid second messengers known as platelet activating factors (PAFs) (10,11).…”

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confidence: 99%

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Amyloid-β₄₂signals tau hyperphosphorylation and compromises neuronal viability by disrupting alkylacylglycerophosphocholine metabolism

Ryan¹,

Whitehead²,

Swayne³

et al. 2009

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

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Perturbation of lipid second messenger networks is associated with the impairment of synaptic function in Alzheimer disease. Underlying molecular mechanisms are unclear. Here, we used an unbiased lipidomic approach to profile alkylacylglycerophosphocholine second messengers in diseased tissue. We found that specific isoforms defined by a palmitic acid (16:0) at the sn-1 position, namely 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (C16:0 PAF) and 1-O-hexadecyl-sn-glycero-3-phosphocholine (C16:0 lyso-PAF), were elevated in the temporal cortex of Alzheimer disease patients, transgenic mice expressing human familial diseasemutant amyloid precursor protein, and human neurons directly exposed to amyloid-␤ 42 oligomers. Acute intraneuronal accumulation of C16:0 PAF but not C16:0 lyso-PAF initiated cyclindependent kinase 5-mediated hyperphosphorylation of tau on Alzheimer disease-specific epitopes. Chronic elevation caused a caspase 2 and 3/7-dependent cascade resulting in neuronal death. Pharmacological inhibition of C16:0 PAF signaling, or molecular strategies increasing hydrolysis of C16:0 PAF to C16:0 lyso-PAF, protected human neurons from amyloid-␤ 42 toxicity. Together, these data provide mechanistic insight into how disruptions in lipid metabolism can determine neuronal response to accumulating oligomeric amyloid-␤ 42.Alzheimer disease ͉ glycerophosphocholine ͉ lipidomics ͉ T he aberrant processing of the amyloid precursor protein to different assemblies of amyloid ␤ (A␤) peptides ranging from 37 to 42 amino acids is an early and necessary prerequisite for the development of Alzheimer disease (AD) (1). The ''amyloid cascade hypothesis'' defines generation of these smaller, toxic A␤ fragments, specifically soluble A␤ 42 oligomers, as the root cause of AD (1). The severity of AD progression, however, is highly correlated with the rate of abnormal tau processing (2). Underlying molecular mechanisms linking A␤ 42 biogenesis to the aggregation of normally soluble tau proteins into hyperphosphorylated oligomers remain elusive.A␤ 42 can activate cytosolic phospholipase A 2 (cPLA 2 ) (3, 4), a Group IVa PLA 2 that preferentially hydrolyzes arachidonic acid from the sn-2 position of 1-O-alkyl-2-arachidonoyl-and 1-O-acyl-2-arachidonoyl-glycerophospholipids (5). Inhibiting cPLA 2 activation completely attenuates A␤ 42 neurotoxicity; blocking the different metabolic arms of the arachidonic acid cascade confers only partial protection (3,4,6). Little is known about the fate of the glycerophospholipid backbone following the release of arachidonic acid by cPLA 2 , although accumulation of choline-containing lipids is associated with accelerated cognitive decline in AD (7,8). The alkyl-lyso-glycerophosphocholines and lysophosphatidylcholines (LPCs) are of particular interest (Fig. S1). These metabolites are biologically active in their own right and can be further modified by lysophosphatidylcholine acyltransferases (LPCATs). LPCAT activity also increases in AD (9), notably in the posterior-temporal entorhinal cortex, a r...

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Section: Discussionsupporting

confidence: 53%

mentioning

confidence: 99%

Amyloid-β₄₂signals tau hyperphosphorylation and compromises neuronal viability by disrupting alkylacylglycerophosphocholine metabolism

Ryan¹,

Whitehead²,

Swayne³

et al. 2009

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

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“…The hydrolysis of membrane phosphatidylcholine releases free choline that is a substrate for the synthesis of acetylcholine, an important neurotransmitter that has been implicated in the pathophysiology of AD. Changes in PLA2 activity have been demonstrated in various neuropsychiatric disorders such as temporal lobe epilepsy [60] , schizophrenia [61][62][63][64] , and AD [65,66] . Experimental models have shown that PLA2 influences APP processing and secretion.…”

Section: Platelet Phospholipase A2 Activitymentioning

confidence: 99%

Platelet biomarkers in Alzheimer’s disease

Talib

Joaquim²,

Forlenza³

2012

WJP

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The search for diagnostic and prognostic markers in Alzheimer's disease (AD) has been an area of active research in the last decades. Biochemical markers are correlates of intracerebral changes that can be identified in biological fluids, namely: peripheral blood (total blood, red and white blood cells, platelets, plasma and serum), saliva, urine and cerebrospinal fluid. An important feature of a biomarker is that it can be measured objectively and evaluated as (1) an indicator of disease mechanisms (markers of core pathogenic processes or the expression of downstream effects of these processes), or (2) biochemical responses to pharmacological or therapeutic intervention, which can be indicative of disease modification. Platelets have been used in neuropharmacological models since the mid-fifties, as they share several homeostatic functions with neurons, such as accumulation and release of neurotransmitters, responsiveness to variations in calcium concentration, and expression of membrane-bound compounds. Recent studies have shown that platelets also express several components related to the pathogenesis of AD, in particular to the amyloid cascade and the regulation of oxidative stress: thus they can be used in the search for biomarkers of the disease process. For instance, platelets are the most important source of circulating forms of the amyloid precursor protein and other important proteins such as Tau and glycogen synthase kinase-3B. Moreover, platelets express enzymes involved in membrane homeostasis (e.g., phospholipase A2), and markers of the inflammatory process and oxidative stress. In this review we summarize the available literature and discuss evidence concerning the potential use of platelet markers in AD.

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“…As the Pla2 activity is significantly reduced in brain tissues [38,60] as well cerebrospinal fluid of patients with AD when compared to controls [42], we investigated whether LiCl would modulate Pla2 mRNA levels and/or enzymatic activity.…”

Section: Discussionmentioning

confidence: 99%

“…Protein concentration was determined with the Bio-Rad DC Protein Assay (Bio-Rad, Hercules, CA, USA), modified from Lowry et al [55]. Briefly, the substrate used was L-α-1-palmitoyl-2-arachidonyl-phosphatidyl-choline labeled with [l- 14 C] in the arachidonyl tail at position sn-2 ( 14 C-PC) (48 mCi/ mmol specific activity, PerkinElmer, Boston, MA) [56][57][58][59][60], with slight modifications. Prior to the enzymatic reaction, a mixture of arachidonyl-l-14 C-PC and toluol-ethanolbutylhydroxytoluol antioxidants (1:10, v/v) was evaporated under a nitrogen stream (0.075 μCi per sample), resuspended in a solution of 0.3 mg/mL BSA in ultrapure water and homogenized by sonication.…”

Section: Radioenzymatic Analysis Of Pla2 Activitymentioning

confidence: 99%

Lithium activates brain phospholipase A2 and improves memory in rats: implications for Alzheimer’s disease

Mury

Silva

Barbosa

et al. 2015

Eur Arch Psychiatry Clin Neurosci

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a significant perdurability of long-term memory, which correlated with increased transcriptional and enzymatic activities of certain members of the Pla2 family (iPla2 and sPla2) after the chronic lithium treatment. Our data suggest new possible targets of lithium, add more information on its pharmacological activity and reinforce the possible use of low doses of lithium for the treatment of neurodegenerative conditions such as the Alzheimer's disease.

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Phospholipid‐Metabolizing Enzymes in Alzheimer's Disease: Increased Lysophospholipid Acyltransferase Activity and Decreased Phospholipase A₂ Activity

Cited by 121 publications

References 34 publications

Amyloid-β₄₂signals tau hyperphosphorylation and compromises neuronal viability by disrupting alkylacylglycerophosphocholine metabolism

Amyloid-β₄₂signals tau hyperphosphorylation and compromises neuronal viability by disrupting alkylacylglycerophosphocholine metabolism

Platelet biomarkers in Alzheimer’s disease

Lithium activates brain phospholipase A2 and improves memory in rats: implications for Alzheimer’s disease

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Phospholipid‐Metabolizing Enzymes in Alzheimer's Disease: Increased Lysophospholipid Acyltransferase Activity and Decreased Phospholipase A2 Activity

Cited by 121 publications

References 34 publications

Amyloid-β42signals tau hyperphosphorylation and compromises neuronal viability by disrupting alkylacylglycerophosphocholine metabolism

Amyloid-β42signals tau hyperphosphorylation and compromises neuronal viability by disrupting alkylacylglycerophosphocholine metabolism

Platelet biomarkers in Alzheimer’s disease

Lithium activates brain phospholipase A2 and improves memory in rats: implications for Alzheimer’s disease

Contact Info

Product

Resources

About

Phospholipid‐Metabolizing Enzymes in Alzheimer's Disease: Increased Lysophospholipid Acyltransferase Activity and Decreased Phospholipase A₂ Activity

Amyloid-β₄₂signals tau hyperphosphorylation and compromises neuronal viability by disrupting alkylacylglycerophosphocholine metabolism

Amyloid-β₄₂signals tau hyperphosphorylation and compromises neuronal viability by disrupting alkylacylglycerophosphocholine metabolism