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Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032, USA.
Nature Neuroscience (Impact Factor: 16.1). 06/2008; 11(5):547-54. DOI: 10.1038/nn.2100
Source: PubMed


Synaptic dysfunction caused by oligomeric assemblies of amyloid- peptide (A) has been linked to cognitive deficits in Alzheimer's disease. Here we found that incubation of primary cortical neurons with oligomeric A decreases the level of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2), a phospholipid that regulates key aspects of neuronal function. The destabilizing effect of A on PtdIns(4,5)P2 metabolism was Ca2+-dependent and was not observed in neurons that were derived from mice that are haploinsufficient for Synj1. This gene encodes synaptojanin 1, the main PtdIns(4,5)P2 phosphatase in the brain and at the synapses. We also found that the inhibitory effect of A on hippocampal long-term potentiation was strongly suppressed in slices from Synj1+/-
mice, suggesting that A-induced synaptic dysfunction can be ameliorated by treatments that maintain the normal PtdIns(4,5)P2 balance in the brain.

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Available from: Diego E Berman, Jul 21, 2015
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    • "SM content affects PI(4,5)P2-PLCγ signaling in synaptosomes Alterations in phosphoinositide PI(4,5)P2 levels seem to be at the base of neuronal dysfunction in different cognitive pathological conditions and in aging (Landman et al., 2006; Berman et al., 2008). In turn, phosphoinositide clustering is critically dependent on SM-rich domains (Abe et al., 2012). "
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    ABSTRACT: Niemann-Pick disease type A (NPDA) is a fatal disease due to mutations in the acid sphingomyelinase (ASM) gene, which triggers the abnormal accumulation of sphingomyelin (SM) in lysosomes and the plasma membrane of mutant cells. Although the disease affects multiple organs, the impact on the brain is the most invalidating feature. The mechanisms responsible for the cognitive deficits characteristic of this condition are only partially understood. Using mice lacking the ASM gene (ASMKO), a model system in NPDA research, we here report that high sphingomyelin levels in mutant neurons lead to low synaptic levels of phosphoinositide PI(4,5)P2 and reduced activity of its hydrolyzing phosphatase PLCγ, which are key players in synaptic plasticity events. In addition, mutant neurons have reduced levels of membrane-bound MARCKS, a protein required for PI(4,5)P2 membrane clustering and hydrolysis. Intracerebroventricular infusion of a peptide that mimics the effector domain of MARCKS increases the content of PI(4,5)P2 in the synaptic membrane and ameliorates behavioral abnormalities in ASMko mice.
    Neurobiology of Disease 09/2014; 73. DOI:10.1016/j.nbd.2014.09.008 · 5.08 Impact Factor
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    • "Enhancing apolipoprotein E (ApoE)-dependent trafficking of PUFAs from neurons to glia in APP/presenilin 1 (PS1) transgenic mice changes the phospholipid composition of synaptosomes, increases Aβ42 clearance, and reverses learning and memory impairment (Igbavboa et al., 2002; Cramer et al., 2012). Conversely, inhibition or genetic ablation of phospholipase D2 (PLD2) (Figure 2B), the group IV isoform of PLA2 (cPLA2) (Figure 2B), or synaptojamin, the primary phosphoinositide PI(4,5)P2 phosphatase also confers synaptic protection, reduces Aβ42 biosynthesis, and rescues memory deficits in APP transgenics (Berman et al., 2008; Sanchez-Mejia et al., 2008; Oliveira et al., 2010). "
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    ABSTRACT: Not all of the mysteries of life lie in our genetic code. Some can be found buried in our membranes. These shells of fat, sculpted in the central nervous system into the cellular (and subcellular) boundaries of neurons and glia, are themselves complex systems of information. The diversity of neural phospholipids, coupled with their chameleon-like capacity to transmute into bioactive molecules, provides a vast repertoire of immediate response second messengers. The effects of compositional changes on synaptic function have only begun to be appreciated. Here, we mined 29 neurolipidomic datasets for changes in neuronal membrane phospholipid metabolism in Alzheimer's Disease (AD). Three overarching metabolic disturbances were detected. We found that an increase in the hydrolysis of platelet activating factor precursors and ethanolamine-containing plasmalogens, coupled with a failure to regenerate relatively rare alkyl-acyl and alkenyl-acyl structural phospholipids, correlated with disease severity. Accumulation of specific bioactive metabolites [i.e., PC(O-16:0/2:0) and PE(P-16:0/0:0)] was associated with aggravating tau pathology, enhancing vesicular release, and signaling neuronal loss. Finally, depletion of PI(16:0/20:4), PI(16:0/22:6), and PI(18:0/22:6) was implicated in accelerating Aβ42 biogenesis. Our analysis further suggested that converging disruptions in platelet activating factor, plasmalogen, phosphoinositol, phosphoethanolamine (PE), and docosahexaenoic acid metabolism may contribute mechanistically to catastrophic vesicular depletion, impaired receptor trafficking, and morphological dendritic deformation. Together, this analysis supports an emerging hypothesis that aberrant phospholipid metabolism may be one of multiple critical determinants required for Alzheimer disease conversion.
    Frontiers in Physiology 07/2013; 4:168. DOI:10.3389/fphys.2013.00168 · 3.53 Impact Factor
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    • "The longer Aβ1-42 (Aβ42) proteolytic variant is more hydrophobic and tends to aggregate into plaques (Brody et al., 2008). In the experimental setting, Aβ may be synaptotoxic (Claeysen et al., 2012; Koffie et al., 2012), neurotoxic (Walsh et al., 2002), disrupt cellular membranes (Berman et al., 2008), interfere with mitochondrial function (Parihar and Brewer, 2010), activate NMDA receptors (Texido et al., 2011), or activate microglia (Stalder et al., 1999). Importantly, both endogenously and exogenously elevated Aβ may lead to neuronal death and behavioral dysfunction (Mattson, 2004). "
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    ABSTRACT: Traumatic brain injury (TBI) survivors frequently suffer from life-long deficits in cognitive functions and a reduced quality of life. Axonal injury, observed in most severe TBI patients, results in accumulation of amyloid precursor protein (APP). Post-injury enzymatic cleavage of APP can generate amyloid-β (Aβ) peptides, a hallmark finding in Alzheimer’s disease (AD). At autopsy, brains of AD and a subset of TBI victims display some similarities including accumulation of Aβ peptides and neurofibrillary tangles of hyperphosphorylated tau proteins. Most epidemiological evidence suggests a link between TBI and AD, implying that TBI has neurodegenerative sequelae. Aβ peptides and tau may be used as biomarkers in interstitial fluid (ISF) using cerebral microdialysis and/or cerebrospinal fluid (CSF) following clinical TBI. In the present review, the available clinical and experimental literature on Aβ peptides and tau as potential biomarkers following TBI is comprehensively analyzed. Elevated CSF and ISF tau protein levels have been observed following severe TBI and suggested to correlate with clinical outcome. Although Aβ peptides are produced by normal neuronal metabolism, high levels of long and/or fibrillary Aβ peptides may be neurotoxic. Increased CSF and/or ISF Aβ levels post-injury may be related to neuronal activity and/or the presence of axonal injury. The heterogeneity of animal models, clinical cohorts, analytical techniques and the complexity of TBI in available studies make the clinical value of tau and Aβ as biomarkers uncertain at present. Additionally, the link between early post-injury changes in tau and Aβ peptides and the future risk of developing AD remains unclear. Future studies using e.g. rapid biomarker sampling combined with enhanced analytical techniques and/or novel pharmacological tools could provide additional information on the importance of Aβ peptides and tau protein in both the acute pathophysiology and long-term consequences of TBI.
    Frontiers in Neurology 06/2013; 4:79. DOI:10.3389/fneur.2013.00079
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