Eliezer Masliah

University of California, San Diego, San Diego, California, United States

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Publications (795)4696.55 Total impact

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    ABSTRACT: Pathologic amyloid accumulates in the CNS or in peripheral organs, yet the mechanism underlying the targeting of systemic amyloid deposits is unclear. Serum amyloid A (SAA) 1 and 2 are produced predominantly by the liver and form amyloid most commonly in the spleen, liver, and kidney. In contrast, SAA3 is produced primarily extrahepatically and has no causal link to amyloid formation. Here, we identified 8 amyloidosis cases with amyloid composed of SAA3 expanding the uterine wall of goats with near-term fetuses. Uterine amyloid accumulated in the endometrium, only at the site of placental attachment, compromising maternal-fetal gas and nutrient exchange and leading to fetal ischemia and death. No other organ contained amyloid. SAA3 mRNA levels in the uterine endometrium were as high as SAA2 in the liver, yet mass spectrometry of the insoluble uterine peptides identified SAA3 as the predominant protein, and not SAA1 or SAA2. These findings suggest that high local SAA3 production led to deposition at this unusual site. Although amyloid A (AA) amyloid deposits typically consist of an N-terminal fragment of SAA1 or SAA2, here, abundant C-terminal peptides indicated that the uterine amyloid was largely composed of full-length SAA3. The exclusive deposition of SAA3 amyloid in the uterus, together with elevated uterine SAA3 transcripts, suggests that the uterine amyloid deposits were due to locally produced SAA3. This is the first report of SAA3 as a cause of amyloidosis and of AA amyloid deposited exclusively in the uterus.-Gaffney, P. M., Barr, B., Rowe, J. D., Bett, C., Drygiannakis, I., Giannitti, F., Trejo, M., Ghassemian, M., Martin, P., Masliah, E., Sigurdson, C. J. Protein profiling of isolated uterine AA amyloidosis causing fetal death in goats. © FASEB.
    The FASEB Journal 11/2014; · 5.70 Impact Factor
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    ABSTRACT: Mice overexpressing human alpha-synuclein in oligodendrocytes (MBP1-α-syn) recapitulate some key functional and neuropathological features of multiple system atrophy (MSA). Whether or not these mice develop severe autonomic failure, which is a key feature of human MSA, remains unknown. We explored cardiovascular autonomic regulation using long-term blood pressure (BP) radiotelemetry and pharmacological testing. We instrumented 12 MBP1-α-syn mice and 11 wild-type mice aged 9 months for radiotelemetry. Animals were tested with atropine, metoprolol, clonidine, and trimethaphan at 9 and 12 months age. We applied spectral and cross-spectral analysis to assess heart rate (HR) and BP variability. At 9 months of age daytime BP (transgenic: 101 ± 2 vs. wild type: 99 ± 2 mmHg) and HR (497 ± 11 vs. 505 ± 16 beats/min) were similar. Circadian BP and HR rhythms were maintained. Nighttime BP (109 ± 2 vs. 108 ± 2 mmHg) and HR (575 ± 15 vs. 569 ± 14 beats/min), mean arterial BP responses to trimethaphan (-21 ± 8 vs. -10 ± 5 mmHg, P = 0.240) and to clonidine (-8 ± 3 vs. -5 ± 2 mmHg, P = 0.314) were similar. HR responses to atropine (+159 ± 24 vs. +146 ± 22 beats/min), and to clonidine (-188 ± 21 vs. -163 ± 33 beats/min) did not differ between strains. Baroreflex sensitivity (4 ± 1 vs. 4 ± 1 msec/mmHg) and HR variability (total power, 84 ± 17 vs. 65 ± 21 msec²) were similar under resting conditions and during pharmacological testing. Repeated measurements at 12 months of age provided similar results. In mice, moderate overexpression of human alpha-synuclein in oligodendrocytes is not sufficient to induce overt autonomic failure. Additional mechanisms may be required to express the autonomic failure phenotype including higher levels of expression or more advanced age. © 2014 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.
    Physiological reports. 11/2014; 2(11).
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    ABSTRACT: SNCA/alpha-synuclein aggregation plays a crucial role in synucleinopathies such as Parkinson disease and dementia with Lewy bodies. Aggregating and non-aggregating SNCA species are degraded by the autophagy-lysosomal pathway (ALP). Previously, we have shown that the ALP is not only responsible for SNCA degradation but is also involved in the intracellular aggregation process of SNCA. An additional role of extracellular SNCA in the pathology of synucleinopathies substantiating a prion-like propagation hypothesis has been suggested since released SNCA species and spreading of SNCA pathology throughout neural cells have been observed. However, the molecular interplay between intracellular pathways, SNCA aggregation, release, and response of the local microenvironment remains unknown. Here, we attributed SNCA-induced toxicity mainly to secreted species in a cell culture model of SNCA aggregation and in SNCA transgenic mice: We showed that ALP inhibition by BafilomycinA1 reduced intracellular SNCA aggregation but increased secretion of smaller oligomers that exacerbated microenvironmental response including uptake, inflammation and cellular damage. Low-aggregated SNCA was predominantly released by exosomes and RAB11A-associated pathways whereas high-aggregated SNCA was secreted by membrane shedding. In summary, our study revealed a novel role of the ALP by linking protein degradation to non-classical secretion for toxic SNCA species. Thus, impaired ALP in the diseased brain not only limits intracellular degradation of misfolded proteins, but also leads to a detrimental microenvironmental response due to enhanced SNCA secretion. These findings suggest that the major toxic role of SNCA is related to its extracellular species and further supports a protective role of intracellular SNCA aggregation.
    Autophagy 10/2014; · 12.04 Impact Factor
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    ABSTRACT: We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (Aβ) plaques. For these "NFT+/Aβ-" brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.
    Acta Neuropathologica 10/2014; · 9.73 Impact Factor
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    ABSTRACT: Neurogranin is a calmodulin binding protein that has been implicated in learning and memory, long-term potentiation and synaptic plasticity. Neurons expressing neurogranin in the cortex degenerate in late stages of Parkinson's Disease with widespread α-synuclein pathology. While analyzing neurogranin gene expression levels through rtPCR in brains of mouse models overexpressing human α-synuclein, we found levels were elevated 2.5 times when compared to nontransgenic animals. Immunohistochemistry in the cortex revealed colocalization between α-synuclein and neurogranin in mouse transgenics when compared to control mice. Coimmunoprecipitation studies in the superior temporal cortex in humans confirmed interaction between α-synuclein and neurogranin, and decreased interaction between α-synuclein and neurogranin was noticed in patients diagnosed with Parkinson's Disease when compared to normal control brains. Additionally, phosphorylated neurogranin levels were also decreased in the human superior temporal cortex in patients diagnosed with Parkinson's Disease and patients diagnosed with Dementia with Lewy Bodies. Here, we show for the first time that neurogranin binds to α-synuclein in the human cortex, and this interaction decreases in Parkinson's Disease along with the phosphorylation of neurogranin, a molecular process thought to be involved in learning and memory.
    Brain Research. 10/2014;
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    ABSTRACT: Macroautophagy (hereafter autophagy) is the major pathway by which macromolecules and organelles are degraded. Autophagy is regulated by the mTOR signaling pathway-the focal point for integration of metabolic information, with mTORC1 playing a central role in balancing biosynthesis and catabolism. Of the various inputs to mTORC1, the amino acid sensing pathway is among the most potent. Based upon transcriptome analysis of neurons subjected to nutrient deprivation, we identified let-7 microRNA as capable of promoting neuronal autophagy. We found that let-7 activates autophagy by coordinately downregulating the amino acid sensing pathway to prevent mTORC1 activation. Let-7 induced autophagy in the brain to eliminate protein aggregates, establishing its physiological relevance for in vivo autophagy modulation. Moreover, peripheral delivery of let-7 anti-miR repressed autophagy in muscle and white fat, suggesting that let-7 autophagy regulation extends beyond CNS. Hence, let-7 plays a central role in nutrient homeostasis and proteostasis regulation in higher organisms.
    Cell metabolism 10/2014; 20(4):626-638. · 17.35 Impact Factor
  • Cassia R Overk, Eliezer Masliah
    Proceedings of the National Academy of Sciences 09/2014; · 9.81 Impact Factor
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    ABSTRACT: Aβ accumulation plays a central role in the pathogenesis of Alzheimer's disease (AD). Recent studies suggest that process of Aβ nucleated polymerization is essential for Aβ fibril formation, pathology spreading and toxicity. Therefore, targeting this process represent an effective therapeutic strategy to slow or block disease progression. To discover compounds that might interfere with the Aβ seeding capacity, toxicity and pathology spreading, we screened a focused library of FDA-approved drugs in vitro using a seeding polymerization assay and identified small molecule inhibitors that specifically interfered with Aβ seeding-mediated fibril growth and toxicity. Mitoxantrone, bithionol and hexachlorophene were found to be the strongest inhibitors of fibril growth and protected primary cortical neuronal cultures against Aβ-induced toxicity. Next, we assessed the effects of these three inhibitors in vivo in the mThy1-APPtg mouse model of AD (8-month-old mice). We found that mitoxantrone and bithionol, but not hexachlorophene, stabilized diffuse amyloid plaques, reduced the levels of Aβ42 oligomers and ameliorated synapse loss, neuronal damage and astrogliosis. Together, our findings suggest that targeting fibril growth and Aβ seeding capacity constitutes a viable and effective strategy for protecting against neurodegeneration and disease progression in AD.
    Neurobiology of Disease 08/2014; · 5.62 Impact Factor
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    ABSTRACT: Background and purposeAnti-retrovirals have improved and extended the life expectancy of patients with human immunodeficiency virus (HIV). However, as this population ages, the prevalence of cognitive alterations is increasing. Aberrant activation of kinases, such as receptor tyrosine kinases (RTKs) and cyclin dependent kinase 5 (CDK5) play a role in the mechanisms of HIV neurotoxicity. Inhibitors of CDK5, such as roscovitine, have neuroprotective effects, however CNS penetration is low. Interestingly, tyrosine kinase inhibitors (TKIs) display some CDK inhibitory activity and ability to cross the blood-brain barrier.Experimental approachWe screened a small group of known TKIs for a candidate with additional CDK5 inhibitory activity and tested the efficacy of the candidate in in vitro and in vivo models of HIV-gp120 neurotoxicity.Key resultsAmong 12 different compounds, sunitinib inhibited CDK5 with an IC50 of 4.2 μM. In silico analysis revealed that, similarly to roscovitine, sunitinib fitted 6 of 10 features of the CDK5 pharmacophore. In a cell-based model, sunitinib reduced CDK5 phosphorylation (pCDK5), calpain-dependent p35/p25 conversion and protected neuronal cells from the toxic effects of gp120. In GFAP-gp120 transgenic mice, sunitinib reduced levels of pCDK5, p35/p25, phosphorylated Tau, as well as ameliorated the neurodegenerative pathology, and promoted in gp120 tg mice.Conclusions & implicationsThis study supports the notion that compounds such as sunitinib with dual kinase inhibitory activity might ameliorate the cognitive impairments associated with the chronic HIV involvement of the CNS. Moreover, repositioning existing small molecule compounds holds promise for the treatment of patients with neurodegenerative disorders.
    British Journal of Pharmacology 08/2014; · 5.07 Impact Factor
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    ABSTRACT: Alzheimer's Disease (AD) and Fronto temporal lobar dementia (FTLD) are common causes of dementia in the aging population for which limited therapeutical options are available. These disorders are associated with Tau accumulation. We have previously shown that CerebrolysinTM (CBL), a neuropeptide mixture with neurotrophic effects, ameliorates the behavioral deficits and neuropathological alterations in amyloid precursor protein (APP) transgenic (tg) mouse model of AD by reducing hyper-phosphorylated Tau. CBL has been tested in clinical trials for AD, however it's potential beneficial effects in FTLD are unknown. For this purpose we sought to investigate the effects of CBL in a tg model of tauopathy. Accordingly, double tg mice expressing mutant Tau under the mThy-1 promoter and GSK3beta (to enhance Tau phosphorylation) were treated with CBL and evaluated neuropathologically.
    BMC Neuroscience 07/2014; 15(1):90. · 3.00 Impact Factor
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    ABSTRACT: Parkinson's disease and Dementia with Lewy bodies are neurodegenerative disorders characterized by accumulation of α-synuclein. Recently, single chain antibodies (scFV) have been developed against individual conformational species of α-syn. Unlike more traditional mAbs, these scFVs will not activate or be endocytosed by Fc receptors. For this study, we investigated a scFV directed against oligomeric α-syn fused to the LDL receptor-binding domain from apoB. The modified scFV showed enhanced brain penetration and was imported into neuronal cells through the ESCRT pathway leading to lysosomal degradation of α-syn aggregates. Further analysis showed the scFV was effective at ameliorating neurodegenerative pathology and behavioral deficits observed in the mouse model of DLB/PD. Thus the apoB modification had the effect of both increasing accumulation of the scFV in the brain and directing scFV/ α-syn complexes for degradation through the ESCRT pathway leading to improved therapeutic potential of immunotherapy.Molecular Therapy (2014); doi:10.1038/mt.2014.129.
    Molecular Therapy 07/2014; · 7.04 Impact Factor
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    ABSTRACT: Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are common neurodegenerative disorders of the aging population, characterized by progressive and abnormal accumulation of α-synuclein (α-syn). Recent studies have shown that C-terminus (CT) truncation and propagation of α-syn play a role in the pathogenesis of PD/DLB. Therefore, we explored the effect of passive immunization against the CT of α-syn in the mThy1-α-syn transgenic (tg) mouse model, which resembles the striato-nigral and motor deficits of PD. Mice were immunized with the new monoclonal antibodies 1H7, 5C1, or 5D12, all directed against the CT of α-syn. CT α-syn antibodies attenuated synaptic and axonal pathology, reduced the accumulation of CT-truncated α-syn (CT-α-syn) in axons, rescued the loss of tyrosine hydroxylase fibers in striatum, and improved motor and memory deficits. Among them, 1H7 and 5C1 were most effective at decreasing levels of CT-α-syn and higher-molecular-weight aggregates. Furthermore, in vitro studies showed that preincubation of recombinant α-syn with 1H7 and 5C1 prevented CT cleavage of α-syn. In a cell-based system, CT antibodies reduced cell-to-cell propagation of full-length α-syn, but not of the CT-α-syn that lacked the 118-126 aa recognition site needed for antibody binding. Furthermore, the results obtained after lentiviral expression of α-syn suggest that antibodies might be blocking the extracellular truncation of α-syn by calpain-1. Together, these results demonstrate that antibodies against the CT of α-syn reduce levels of CT-truncated fragments of the protein and its propagation, thus ameliorating PD-like pathology and improving behavioral and motor functions in a mouse model of this disease.
    The Journal of neuroscience : the official journal of the Society for Neuroscience. 07/2014; 34(28):9441-54.
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    ABSTRACT: Reduced brain-derived neurotrophic factor (BDNF) signaling is considered as a pathogenic event in early Alzheimer's disease (AD), but the influence of apathy and apolipoprotein E ε4 allele (APOE4) on serum BDNF values was not previously investigated in AD. We evaluated serum BDNF levels in AD, amnestic mild cognitive impairment (MCI), and control subjects. Baseline BDNF levels were similar in AD, MCI, and controls. AD patients having apathy showed lower BDNF values than patients without apathy (p < 0.05). After correction for the influence of apathy, APOE4 carriers showed lower BDNF levels (p < 0.01) and MMSE scores (p < 0.01) than non-APOE4 carriers in the subgroup of AD females, but not in males. Significant (p < 0.05) positive correlations between BDNF values and MMSE scores were only observed in subgroups of AD males and of AD patients without apathy. These results are showing the association of apathy and APOE4 with reduced serum BDNF levels in AD, and are suggesting that BDNF reductions might contribute to the worse cognitive performance exhibited by AD apathetic patients and female APOE4 carriers.
    Journal of Alzheimer's disease: JAD 07/2014; · 4.17 Impact Factor
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    ABSTRACT: A thorough investigation of the neurobiology of HIV-induced neuronal dysfunction and its evolving phenotype in the setting of viral suppression has been limited by the lack of validated small animal models to probe the effects of concomitant low level expression of multiple HIV-1 products in disease-relevant cells in the CNS.
    Molecular Neurodegeneration 07/2014; 9(1):26. · 4.01 Impact Factor
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    ABSTRACT: Objective Growing evidence suggests that neurodegenerative diseases are associated with metabolic disorders, but the mechanisms are still unclear. Better comprehension of this issue might provide a new strategy for treatment of neurodegenerative diseases. We investigated possible roles of adiponectin (APN), the antidiabetes protein, in the pathogenesis of α-synucleinopathies.Methods Using biochemical and histological methods, we investigated autopsy brain of α-synucleinopathies including Parkinson's disease (PD) and dementia with Lewy bodies (DLB), and analyzed the effects of APN in cellular and in mouse models of α-synucleinopathies.ResultsWe observed that APN is localized in Lewy bodies derived from α-synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies. In neuronal cells expressing α-synuclein (αS), aggregation of αS was suppressed by treatment with recombinant APN in an AdipoRI-AMP kinase pathway-dependent manner. Concomitantly, phosphorylation and release of αS were significantly decreased by APN, suggesting that APN may be antineurodegenerative. In transgenic mice expressing αS, both histopathology and movement disorder were significantly improved by intranasal treatment with globular APN when the treatment was initiated in the early stage of the disease. In a mouse model, reduced levels of guanosine and inosine monophosphates, both of which are potential stimulators of aggregation of αS, might partly contribute to suppression of aggregation of αS by APN.InterpretationTaken together, APN may suppress neurodegeneration through modification of the metabolic pathway, and could possess a therapeutic potential against α-synucleinopathies.
    Annals of Clinical and Translational Neurology. 07/2014;
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    ABSTRACT: The murine genes encoding transthyretin and retinol binding protein were independently silenced by targeted disruption more than ten years ago. Studies of both strains showed surprisingly little impact on either thyroid function or retinoid metabolism. Silencing TTR led to a relatively mild behavioral phenotype. In order to gain insight into the behavioral effect and determine if it was related to TTR's function as the carrier of retinol binding protein we carried out simultaneous studies with homozygous Rbp4(-/-) and Ttr(-/-) animals 4 to 7 months of age. Both strains showed behavioral differences relative to Ttr and Rbp4 wild type animals and each other. The patterns were discrete for each knockout although there was some overlap. Neuropathologic examination of the cortex and hippocampus revealed cortical and hippocampal (CA3) neuronal loss in both and some degree of gliosis, more pronounced in the Rbp4(-/-) mice. There also appeared to be a major reduction in proliferating and migration competent cells in the subventricular zone in both strains, which was also more severe in the Rbp4(-/-) mice. This is the first description of behavioral abnormalities in Rbp4(-/-) mice. The data also indicate that it is unlikely that the behaviors seen in Ttr(-/-) mice are related to its function as an RBP carrier.
    Neuroscience 06/2014; · 3.12 Impact Factor
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    ABSTRACT: In dementia with Lewy bodies (DLB) abnormal interactions between alpha-synuclein (alpha-syn) and beta amyloid (Abeta) result in selective degeneration of neurons in the neocortex, limbic system and striatum. However, factors rendering these neurons selectively vulnerable have not been fully investigated. The metabotropic glutamate receptor 5 (mGluR5) has been shown to be up regulated in DLB and might play a role as a mediator of the neurotoxic effects of Abeta and alpha-syn in vulnerable neuronal populations. In this context, the main objective of the present study was to investigate the role of mGluR5 as a mediator of the neurotoxic effects of alpha-syn and Abeta in the hippocampus.
    Molecular Neurodegeneration 05/2014; 9(1):18. · 4.01 Impact Factor
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    ABSTRACT: Alzheimer's Disease (AD) is characterized by widespread neurodegeneration throughout the association cortex and limbic system, deposition of Aβ in the neuropil and around the blood vessels, and formation of neurofibrillary tangles. The endopeptidase neprilysin has been successfully used to reduce the accumulation of Aβ following intra-cranial viral vector delivery or ex vivo manipulated intra-cranial delivery. These therapies have relied on direct injections into the brain, whereas a clinically desirable therapy would involve i.v infusion of a recombinant enzyme. We previously characterized a recombinant neprilysin that contained a 38 amino acid brain-targeting domain. Recombinant cell lines have been generated expressing this brain-targeted enzyme (ASN12). In this report, we characterize the ASN12 recombinant protein for pharmacology in a mouse as well as efficacy in two APPtg mouse models of AD. The recombinant ASN12 transited to the brain with a t1/2 of 24 hours and accumulated to 1.7% of injected dose at 24 hours following i.v. delivery. We examined pharmacodynamics in the tg2576 APPtg mouse with the prion promoter APP695 SWE mutation and in the Line41 mThy1 APP751 mutation mouse. Treatment of either APPtg mouse resulted in reduced Aβ, increased neuronal synapses and improved learning and memory. In addition, the Line41 APPtg mice showed increased levels of c-terminal NPY fragments and increased neurogenesis. These results suggest that the recombinant brain-targeted neprilysin, ASN12, may be an effective treatment for AD and warrant further investigation in clinical trials.
    Journal of Biological Chemistry 05/2014; · 4.65 Impact Factor
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    ABSTRACT: Pathologic amyloid accumulates in the central nervous system or in peripheral organs, yet the mechanism underlying the organ tropism of systemic amyloid is unclear. Serum amyloid A (SAA), which is produced predominantly by the liver, assembles into amyloid most commonly in the spleen, liver and kidneys. Here we identified AA amyloidosis cases in which abundant amyloid deposits expanded only the uterine wall of eight goats with late term fetal death. Uterine amyloid accumulated in the endometrium at the site of placental attachment, compromising maternal-fetal gas and nutrient exchange and leading to fetal ischemia. No other organ contained amyloid. Although AA amyloidosis is typically associated with persistently elevated SAA levels from chronic inflammation, these goats had only inconsistent mild to moderate inflammation within any organ. The level of SAA mRNA in the uterine endometrium was high and exceeded levels in liver of some animals, suggesting that local SAA production contributed to the highly unusual deposition site. Mass spectrometry analysis of the insoluble endometrial peptides identified SAA3 as the predominant protein. Although AA amyloid deposits often consist of an N-terminal fragment of the full length SAA protein, abundant C-terminal peptides indicated that the uterine amyloid was largely composed of full length AA. The exclusive deposition of AA amyloid in the uterus, together with high uterine SAA transcript levels, suggest here that the AA organ tropism was caused by locally produced SAA.
    XIVth International Symposium on Amyloidosis (International Society of Amyloidosis), Indianapolis, Indiana; 04/2014

Publication Stats

40k Citations
4,696.55 Total Impact Points

Institutions

  • 1989–2014
    • University of California, San Diego
      • • Department of Medicine
      • • Department of Pathology
      • • Department of Neurosciences
      • • Department of Psychiatry
      San Diego, California, United States
  • 2013
    • University of Melbourne
      • Department of Psychiatry
      Melbourne, Victoria, Australia
    • Johns Hopkins University
      Baltimore, Maryland, United States
    • Tokyo Metropolitan Institute of Medical Science
      • Department of Sensory and Motor Systems
      Tokyo, Tokyo-to, Japan
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      Erlangen, Bavaria, Germany
  • 2010–2013
    • Konkuk University
      • School of Medicine
      Sŏul, Seoul, South Korea
    • Meritorious Autonomous University of Puebla
      • Laboratorio de Neuropsiquiatría
      Ejido Puebla, Baja California, Mexico
    • University of Southern California
      • Department of Medicine
      Los Angeles, CA, United States
    • Brigham and Women's Hospital
      • Department of Medicine
      Cambridge, MA, United States
    • Elan Pharmaceuticals
      Dublin, Leinster, Ireland
  • 2009–2013
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 2008–2013
    • Georgetown University
      • • Department of Biochemistry and Molecular and Cellular Biology
      • • Department of Neuroscience
      Washington, Washington, D.C., United States
  • 2004–2013
    • Sanford-Burnham Medical Research Institute
      • Del E. Webb Neuroscience, Aging and Stem Cell Research Center
      La Jolla, CA, United States
    • Azienda Ospedaliera Niguarda Ca' Granda
      Milano, Lombardy, Italy
    • VA San Diego Healthcare System
      San Diego, California, United States
  • 2002–2013
    • National University (California)
      San Diego, California, United States
  • 2012
    • Universitätsklinikum Erlangen
      Erlangen, Bavaria, Germany
    • Aarhus University
      • Department of Biomedicine
      Aars, Region North Jutland, Denmark
    • Loma Linda University
      • Department of Neurology
      Loma Linda, CA, United States
    • Cleveland Clinic
      • Lou Ruvo Center for Brain Health
      Cleveland, OH, United States
  • 2009–2012
    • École Polytechnique Fédérale de Lausanne
      • • Faculté des Sciences de la Vie
      • • Laboratoire de neurobiologie moléculaire et neuroprotéomique
      Lausanne, VD, Switzerland
  • 1996–2012
    • University of California, San Francisco
      • • Department of Neurology
      • • Department of Cellular and Molecular Pharmacology
      San Francisco, California, United States
  • 1994–2012
    • University of California, Los Angeles
      • • Department of Neurology
      • • Department of Pathology and Laboratory Medicine
      • • Department of Neurobiology
      • • Brain Research Institute
      Los Angeles, CA, United States
    • Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
      Tlalpam, The Federal District, Mexico
  • 2010–2011
    • Harvard Medical School
      • Department of Neurology
      Boston, Massachusetts, United States
  • 2008–2011
    • Tel Aviv University
      • • Department of Neurology
      • • Faculty of Life Sciences
      Tel Aviv, Tel Aviv, Israel
  • 2005–2011
    • Massachusetts General Hospital
      • Martinos Center for Biomedical Imaging
      Boston, MA, United States
    • Beth Israel Deaconess Medical Center
      • Division of Viral Pathogenesis
      Boston, MA, United States
    • University of Pittsburgh
      • Department of Pathology
      Pittsburgh, PA, United States
  • 2002–2011
    • University of Washington Seattle
      • • Department of Pathology
      • • Department of Pharmacology
      • • Department of Neurology
      Seattle, WA, United States
  • 2006–2010
    • Tokyo Metropolitan Institute
      Edo, Tōkyō, Japan
    • Banner Sun Health Research Institute
      Sun City, Arizona, United States
  • 2004–2010
    • Stanford University
      • Department of Neurology and Neurological Sciences
      Stanford, CA, United States
  • 2004–2009
    • Universität Regensburg
      • Lehrstuhl für Neurologie
      Regensburg, Bavaria, Germany
  • 1993–2007
    • The Scripps Research Institute
      • • Department of Molecular and Cellular Neuroscience
      • • Department of Molecular and Experimental Medicine
      La Jolla, CA, United States
  • 1997–2006
    • Naval Medical Center San Diego
      • Department of Pathology
      San Diego, California, United States
  • 2003–2005
    • Salk Institute
      • Laboratory of Genetics
      La Jolla, CA, United States
  • 2002–2004
    • Kyoto University
      • Institute for Chemical Research
      Kyoto, Kyoto-fu, Japan
  • 1998–2004
    • University of Bologna
      • • Department of Experimental, Diagnostic and Specialty Medicine DIMES
      • • School of Medicine
      Bolonia, Emilia-Romagna, Italy
    • University of San Diego
      San Diego, California, United States
  • 2001
    • Hannover Medical School
      • Institute for Pathology
      Hannover, Lower Saxony, Germany
  • 2000
    • Ospedali Riuniti di Bergamo
      Bérgamo, Lombardy, Italy
  • 1999
    • Gyeongsang National University
      • Department of Psychiatry
      Shinshū, South Gyeongsang, South Korea
  • 1995
    • Hungarian Academy of Sciences
      • MTA Institute of Experimental Medicine
      Budapeŝto, Budapest, Hungary
    • McGill University
      • Department of Pharmacology and Therapeutics
      Montréal, Quebec, Canada
  • 1993–1994
    • The University of Tokyo
      Tōkyō, Japan
  • 1992
    • Rutgers, The State University of New Jersey
      New Brunswick, New Jersey, United States