Eliezer Masliah

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

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Publications (869)5401.97 Total impact

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    ABSTRACT: Parkinson's disease (PD) is a multisystem disorder, involving several monoaminergic neurotransmitter systems resulting in a broad range of motor and non-motor symptoms. Pathological hallmarks of PD are the loss of dopaminergic neurons and the accumulation of alpha-synuclein, however also being present in the serotonergic raphe nuclei early in the disease course. The dysfunction of the serotonergic system projecting to the hippocampus might contribute to early non-motor symptoms such as anxiety and depression. The adult hippocampal dentate gyrus (DG), a unique niche of the forebrain continuously generating new neurons, may particularly present enhanced susceptibility towards accumulating alpha-synuclein levels. The underlying molecular mechanisms in the context of neuronal maturation and survival of new-born neurons are yet not well understood. To characterize the effects of overexpression of human full-length alpha-synuclein on hippocampal cellular and synaptic plasticity, we used a recently generated BAC alpha-synuclein transgenic rat model showing important features of PD such as widespread and progressive alpha-synuclein aggregation pathology, dopamine loss and age-dependent motor decline. At the age of four months, thus prior to the occurrence of the motor phenotype, we observed a profoundly impaired dendritogenesis of neuroblasts in the hippocampal DG resulting in severely reduced survival of adult new-born neurons. Diminished neurogenesis concurred with a serotonergic deficit in the hippocampus as defined by reduced levels of serotonin (5-HT) 1B receptor, decreased 5-HT neurotransmitter levels, and a loss of serotonergic nerve terminals innervating the DG/CA3 subfield, while the number of serotonergic neurons in the raphe nuclei remained unchanged. Moreover, alpha-synuclein overexpression reduced proteins involved in vesicle release, in particular synapsin-1 and Rab3 interacting molecule (RIM3), in conjunction with an altered ultrastructural architecture of hippocampal synapses. Importantly, BAC alpha-synuclein rats showed an early anxiety-like phenotype consisting of reduced exploratory behavior and feeding. Taken together, these findings imply that accumulating alpha-synuclein severely affects hippocampal neurogenesis paralleled by impaired 5-HT neurotransmission prior to the onset of aggregation pathology and overt motor deficits in this transgenic rat model of PD.
    Neurobiology of Disease 11/2015; 85. DOI:10.1016/j.nbd.2015.10.021 · 5.08 Impact Factor

  • Neurobiology of Disease 11/2015; DOI:10.1016/j.nbd.2015.11.015 · 5.08 Impact Factor
  • Elvira Valera · Brian Spencer · Eliezer Masliah ·
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    ABSTRACT: Disease-modifying alternatives are sorely needed for the treatment of neurodegenerative disorders, a group of diseases that afflict approximately 50 million Americans annually. Immunotherapy is one of the most developed approaches in this direction. Vaccination against amyloid-β, α-synuclein, or tau has been extensively explored, specially as the discovery that these proteins may propagate cell-to-cell and be accessible to antibodies when embedded into the plasma membrane or in the extracellular space. Likewise, the use of passive immunization approaches with specific antibodies against abnormal conformations of these proteins has also yielded promising results. The clinical development of immunotherapies for Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, and other neurodegenerative disorders is a field in constant evolution. Results to date suggest that immunotherapy is a promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and prion-like propagation of toxic protein aggregates. Here we provide an overview of the most novel and relevant immunotherapeutic advances targeting amyloid-β in Alzheimer's disease, α-synuclein in Alzheimer's disease and Parkinson's disease, and tau in Alzheimer's disease and frontotemporal dementia.
    Journal of the American Society for Experimental NeuroTherapeutics 10/2015; DOI:10.1007/s13311-015-0397-z · 5.05 Impact Factor
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    ABSTRACT: Impaired autophagy has been implicated in many neurodegenerative diseases, such as Parkinson's disease (PD), and might be responsible for deposition of aggregated proteins in neurons. However, little is known about how neuronal autophagy and clearance of aggregated proteins are regulated. Here, we show a role for Toll-like receptor 2 (TLR2), a pathogen-recognizing receptor in innate immunity, in regulation of neuronal autophagy and clearance of α-synuclein, a protein aggregated in synucleinopathies, including in PD. Activation of TLR2 resulted in the accumulation of α-synuclein aggregates in neurons as a result of inhibition of autophagic activity through regulation of the AKT/mTOR pathway. In contrast, inactivation of TLR2 resulted in autophagy activation and increased clearance of neuronal α-synuclein, and hence reduced neurodegeneration, in transgenic mice and in in vitro models. These results uncover roles of TLR2 in regulating neuronal autophagy and suggest that the TLR2 pathway may be targeted for autophagy activation strategies in treating neurodegenerative disorders.
    Cell Reports 10/2015; 13(4). DOI:10.1016/j.celrep.2015.09.044 · 8.36 Impact Factor
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    ABSTRACT: Accumulation of α-synuclein (α-syn) into insoluble aggregates occurs in several related disorders collectively referred to as synucleinopathies. To date, studies have used neural stem cells (NSCs) to examine questions about α-syn propagation, but have overlooked the therapeutic potential of NSC transplantation to modulate cognition in disorders such as dementia with Lewy bodies or Parkinson's disease dementia. Here, we show that striatal transplantation of NSCs into aged α-syn transgenic mice significantly improves performance in multiple cognitive and motor domains. This recovery is associated with NSC expression of brain-derived neurotrophic factor (BDNF), which restores depleted levels and modulates dopaminergic and glutamatergic systems. Most importantly, transplantation of BDNF-depleted NSCs fails to improve behavior, whereas AAV-mediated BDNF delivery mimics the benefits of NSC transplantation, supporting a critical role for this neurotrophin in functional improvement. Thus, NSC transplantation could offer a promising approach to treat the understudied yet devastating cognitive components of many synucleinopathies.
    Stem Cell Reports 10/2015; DOI:10.1016/j.stemcr.2015.09.008 · 5.37 Impact Factor
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    ABSTRACT: Systemic amyloid A (AA) amyloidosis is highly prevalent (34%) in endangered island foxes (Urocyon littoralis) and poses a risk to species recovery. Although elevated serum AA (SAA) from prolonged or recurrent inflammation predisposes to AA amyloidosis, additional risk factors are poorly understood. Here we define the severity of glomerular and medullary renal amyloid and identify risk factors for AA amyloidosis in 321 island foxes necropsied from 1987 through 2010. In affected kidneys, amyloid more commonly accumulated in the medullary interstitium than in the glomeruli (98% [n = 78 of 80] vs 56% [n = 45], respectively; P < .0001), and medullary deposition was more commonly severe (19% [n = 20 of 105]) as compared with glomeruli (7% [n = 7]; P = .01). Univariate odds ratios (ORs) of severe renal AA amyloidosis were greater for short- and long-term captive foxes as compared with free-ranging foxes (ORs = 3.2, 3.7, respectively; overall P = .05) and for females as compared with males (OR = 2.9; P = .05). Multivariable logistic regression revealed that independent risk factors for amyloid development were increasing age class (OR = 3.8; P < .0001), San Clemente Island subspecies versus San Nicolas Island subspecies (OR = 5.3; P = .0003), captivity (OR = 5.1; P = .0001), and nephritis (OR = 2.3; P = .01). The increased risk associated with the San Clemente subspecies or captivity suggests roles for genetic as well as exogenous risk factors in the development of AA amyloidosis.
    Veterinary Pathology 09/2015; DOI:10.1177/0300985815604725 · 1.87 Impact Factor
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    ABSTRACT: Background: Multiple system atrophy (MSA) is a progressive, neurodegenerative disease characterized by parkinsonism, resistance to dopamine therapy, ataxia, autonomic dysfunction, and pathological accumulation of α-synuclein (α-syn) in oligodendrocytes. Neurosin (kallikrein-6) is a serine protease capable of cleaving α-syn in the CNS, and we have previously shown that lentiviral (LV) vector delivery of neurosin into the brain of a mouse model of dementia with Lewy body/ Parkinson's disease reduces the accumulation of α-syn and improves neuronal synaptic integrity. Results: In this study, we investigated the ability of a modified, systemically delivered neurosin to reduce the levels of α-syn in oligodendrocytes and reduce the cell-to-cell spread of α-syn to glial cells in a mouse model of MSA (MBP-α-syn). We engineered a viral vector that expresses a neurosin genetically modified for increased half-life (R80Q mutation) that also contains a brain-targeting sequence (apoB) for delivery into the CNS. Peripheral administration of the LV-neurosin-apoB to the MBP-α-syn tg model resulted in accumulation of neurosin-apoB in the CNS, reduced accumulation of α-syn in oligodendrocytes and astrocytes, improved myelin sheath formation in the corpus callosum and behavioral improvements. Conclusion: Thus, the modified, brain-targeted neurosin may warrant further investigation as potential therapy for MSA.
    Molecular Neurodegeneration 09/2015; 10(1):48. DOI:10.1186/s13024-015-0043-6 · 6.56 Impact Factor
  • Elvira Valera · Eliezer Masliah ·
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    ABSTRACT: Currently there are no disease-modifying alternatives for the treatment of most neurodegenerative disorders. The available therapies for diseases such as Parkinson's disease (PD), PD dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), in which the protein alpha-synuclein (α-Syn) accumulates within neurons and glial cells with toxic consequences, are focused on managing the disease symptoms. However, using strategic drug combinations and/or multi-target drugs might increase the treatment efficiency when compared with monotherapies. Synucleinopathies are complex disorders that progress through several stages, and toxic α-Syn aggregates exhibit prion-like behavior spreading from cell to cell. Therefore, it follows that these neurodegenerative disorders might require equally complex therapeutic approaches to obtain significant and long-lasting results. Hypothetically, therapies aimed at reducing α-Syn accumulation and cell-to-cell transfer, such as immunotherapy against α-Syn, could be combined with agents that reduce neuroinflammation with potential synergistic outcomes. Here we review the current evidence supporting this type of approach, suggesting that such rational therapy combinations, together with the use of multi-target drugs, may hold promise as the next logical step for the treatment of synucleinopathies. © 2015 International Parkinson and Movement Disorder Society.
    Movement Disorders 09/2015; DOI:10.1002/mds.26428 · 5.68 Impact Factor
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    ABSTRACT: Tauopathies, including frontotemporal dementia (FTD) and Alzheimer's disease (AD), are neurodegenerative diseases in which tau fibrils accumulate. Recent evidence supports soluble tau species as the major toxic species. How soluble tau accumulates and causes neurodegeneration remains unclear. Here we identify tau acetylation at Lys174 (K174) as an early change in AD brains and a critical determinant in tau homeostasis and toxicity in mice. The acetyl-mimicking mutant K174Q slows tau turnover and induces cognitive deficits in vivo. Acetyltransferase p300-induced tau acetylation is inhibited by salsalate and salicylate, which enhance tau turnover and reduce tau levels. In the PS19 transgenic mouse model of FTD, administration of salsalate after disease onset inhibited p300 activity, lowered levels of total tau and tau acetylated at K174, rescued tau-induced memory deficits and prevented hippocampal atrophy. The tau-lowering and protective effects of salsalate were diminished in neurons expressing K174Q tau. Targeting tau acetylation could be a new therapeutic strategy against human tauopathies.
    Nature medicine 09/2015; 21(10). DOI:10.1038/nm.3951 · 27.36 Impact Factor
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    ABSTRACT: HIV-associated neurocognitive disorder (HAND) consists of motor and cognitive dysfunction in a relatively large percentage of patients with AIDS. Prior work has suggested that at least part of the neuronal and synaptic damage observed in HAND may occur due to excessive stimulation of NMDA-type glutamate receptors (NMDARs). Here, we compared pharmacological and genetic manipulation of NMDAR activity using an improved derivative of the NMDAR antagonist memantine, termed NitroMemantine, and the modulatory NMDAR subunit GluN3A in the HIV/gp120 transgenic (tg) mouse model of HAND. Interestingly, we found that while both NitroMemantine and GluN3A have been shown to inhibit NMDAR activity, NitroMemantine protected synapses in gp120-tg mice, but overexpression of GluN3A augmented the damage. Given recent findings in the field, one explanation for this apparently paradoxical result is the location of the NMDARs primarily affected, with NitroMemantine inhibiting predominantly extrasynaptic pathologically activated NMDARs, but GluN3A disrupting normal NMDAR-mediated neuroprotective activity via inhibition of synaptic NMDARs.
    Journal of Molecular Neuroscience 09/2015; DOI:10.1007/s12031-015-0651-1 · 2.34 Impact Factor
  • Cassia R Overk · Edward Rockenstein · Jazmin Florio · Qun Cheng · Eliezer Masliah ·
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    ABSTRACT: Abnormal accumulation of amyloid β (Aβ), α-synuclein (α-syn), and microtubule associated protein tau (tau) have been implicated in neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and Pick's disease (PiD). The mechanisms through which aggregated versions of α-syn, Aβ, and tau may lead to neurodegeneration are not entirely clear, however, there is emerging evidence that neuronal calcium dysregulation is at play. Two-photon microscopy is a powerful tool that can be used to measure in vivo alterations of calcium transients using animal models of neurodegeneration, and when coupled with statistical methods to characterize functional signals, can reveal features that identify and discern between distinct mouse types. We studied four mouse models of neurodegenerative diseases, wild-type (WT) α-syn, E57K α-syn, amyloid precursor protein (APP), and triple-repeat (3R)-Tau and Non-tg littermates using two-photon microscopy. We found that for calcium transients, simple measures such as area under the curve (AUC) and peak width in the 1 Hz whisker pad stimulation paradigm, were significantly increased for WT α-syn, E57K α-syn and APP mice across all cortical depths compared to Non-tg mice. A similar result was found in the 3 Hz paradigm in E57K α-syn mice. Spontaneous calcium transient AUC was significantly higher in WT α-syn mice and lower for APP and 3R Tau mice at 150 μm depth. Going beyond simple measure differences such as group means for AUC, signal peak width, and spontaneous calcium activity counts, we built statistical classifiers to characterize neuronal calcium signals to identify and discern, with quantified measures of confidence, all mouse types. We tested our classifier with FK506, which regulates mitochondrial calcium and found that this drug modulated the WT α-syn calcium transients to such an extent that the classifier easily identified the calcium transients as belonging to Non-tg mice. The coupling of two photon microscopy data and statistical classifiers serves to effectively create a bioassay where the number of animals and scientific resources can be reduced without compromising the results of the experiment. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 09/2015; DOI:10.1016/j.neuroscience.2015.08.068 · 3.36 Impact Factor
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    ABSTRACT: Progressive supranuclear palsy (PSP) is a movement disorder characterized by tau neuropathology where the underlying mechanism is unknown. An SNP (rs1768208 C/T) has been identified as a strong risk factor for PSP. Here, we identified a much higher T-allele occurrence and increased levels of the pro-apoptotic protein appoptosin in PSP patients. Elevations in appoptosin correlate with activated caspase-3 and caspase-cleaved tau levels. Appoptosin overexpression increased caspase-mediated tau cleavage, tau aggregation, and synaptic dysfunction, whereas appoptosin deficiency reduced tau cleavage and aggregation. Appoptosin transduction impaired multiple motor functions and exacerbated neuropathology in tau-transgenic mice in a manner dependent on caspase-3 and tau. Increased appoptosin and caspase-3-cleaved tau were also observed in brain samples of patients with Alzheimer's disease and frontotemporal dementia with tau inclusions. Our findings reveal a novel role for appoptosin in neurological disorders with tau neuropathology, linking caspase-3-mediated tau cleavage to synaptic dysfunction and behavioral/motor defects. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 09/2015; 87(5):963-75. DOI:10.1016/j.neuron.2015.08.020 · 15.05 Impact Factor
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    ABSTRACT: Alzheimer disease (AD) is the most common neurodegenerative disorder and lacks effective disease-modifying therapies. In 2001, we initiated a clinical trial of nerve growth factor (NGF) gene therapy in AD, the first effort at gene delivery in an adult neurodegenerative disorder. This program aimed to determine whether a nervous system growth factor prevents or reduces cholinergic neuronal degeneration in patients with AD. We present postmortem findings in 10 patients with survival times ranging from 1 to 10 years after treatment. To determine whether degenerating neurons in AD retain an ability to respond to a nervous system growth factor delivered after disease onset. Patients in this anatomicopathological study were enrolled in clinical trials from March 2001 to October 2012 at the University of California, San Diego, Medical Center in La Jolla. Ten patients with early AD underwent NGF gene therapy using ex vivo or in vivo gene transfer. The brains of all 8 patients in the first phase 1 ex vivo trial and of 2 patients in a subsequent phase 1 in vivo trial were examined. Brains were immunolabeled to evaluate in vivo gene expression, cholinergic neuronal responses to NGF, and activation of NGF-related cell signaling. In 2 patients, NGF protein levels were measured by enzyme-linked immunosorbent assay. Among 10 patients, degenerating neurons in the AD brain responded to NGF. All patients exhibited a trophic response to NGF in the form of axonal sprouting toward the NGF source. Comparing treated and nontreated sides of the brain in 3 patients who underwent unilateral gene transfer, cholinergic neuronal hypertrophy occurred on the NGF-treated side (P < .05). Activation of cellular signaling and functional markers was present in 2 patients who underwent adeno-associated viral vectors (serotype 2)-mediated NGF gene transfer. Neurons exhibiting tau pathology and neurons free of tau expressed NGF, indicating that degenerating cells can be infected with therapeutic genes, with resultant activation of cell signaling. No adverse pathological effects related to NGF were observed. These findings indicate that neurons of the degenerating brain retain the ability to respond to growth factors with axonal sprouting, cell hypertrophy, and activation of functional markers. Sprouting induced by NGF persists for 10 years after gene transfer. Growth factor therapy appears safe over extended periods and merits continued testing as a means of treating neurodegenerative disorders.
    08/2015; 72(10). DOI:10.1001/jamaneurol.2015.1807
  • Eliezer Masliah · Brian Spencer ·
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    ABSTRACT: Delivery of protein therapeutics to the CNS has proven to be a challenge to due to the presence of the blood-brain barrier (BBB), which prevents the passage of most proteins and large molecules from invading the neuronal space. Recently, we, and others, have developed technologies to circumvent this barrier by targeting receptors on the surface of the endothelial cells of the BBB to facilitate transport of therapeutic proteins. We describe here one such approach for targeting the LDLR by fusion of 38 amino acids from the ApoB protein to a therapeutic protein.
    Methods in molecular biology (Clifton, N.J.) 07/2015; 1324:331-7. DOI:10.1007/978-1-4939-2806-4_21 · 1.29 Impact Factor
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    ABSTRACT: Parkinson's disease, neuropathologically defined by the aggregation of alpha-synuclein, is characterized by neuropsychiatric symptoms such as depression and anxiety preceding the onset of motor symptoms. A loss of serotonergic neurons or their projections into the hippocampus, and alterations in serotonin release may be linked to these symptoms. Here, we investigate the effect of human A53T alpha-synuclein on serotonergic neurons using 12 months old transgenic mice. We detected human alpha-synuclein in the perikarya of brainstem median and dorsal raphe neurons as well as in serotonergic fibers in the hippocampus. Despite intracellular alpha-synuclein accumulation there was no loss of serotonergic neurons in dorsal and median raphe nuclei of A53T alpha-synuclein mice. However, serotonin levels were significantly reduced in the brainstem. Additionally, serotonergic fiber density in the dorsal dentate gyrus was significantly less dense in transgenic mice. Interestingly, we detected a significantly compromised increase of doublecortin+ neuroblasts after chronic treatment with fluoxetine at the site of reduced serotonergic innervation, the infrapyramidal blade of the dorsal dentate gyrus in A53T alpha-synuclein mice. This suggests that alpha-synuclein affects serotonergic projections in a spatially distinct pattern within the hippocampus thereby influencing the response to antidepressant treatment. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 07/2015; 135(3). DOI:10.1111/jnc.13253 · 4.28 Impact Factor
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    ABSTRACT: Evidence from patients with amnesia suggests that recognition memory span tasks engage both long-term memory (i.e., secondary memory) processes mediated by the diencephalic-medial temporal lobe memory system and working memory processes mediated by fronto-striatal systems. Thus, the recognition memory span task may be particularly effective for detecting memory deficits in disorders that disrupt both memory systems. The presence of unique pathology in fronto-striatal circuits in Dementia with Lewy Bodies (DLB) compared to AD suggests that performance on the recognition memory span task might be differentially affected in the two disorders even though they have quantitatively similar deficits in secondary memory. In the present study, patients with autopsy-confirmed DLB or AD, and normal control (NC) participants, were tested on separate recognition memory span tasks that required them to retain increasing amounts of verbal, spatial, or visual object (i.e., faces) information across trials. Results showed that recognition memory spans for verbal and spatial stimuli, but not face stimuli, were lower in patients with DLB than in those with AD, and more impaired relative to NC performance. This was despite similar deficits in the two patient groups on independent measures of secondary memory such as the total number of words recalled from Long-Term Storage on the Buschke Selective Reminding Test. The disproportionate vulnerability of recognition memory span task performance in DLB compared to AD may be due to greater fronto-striatal involvement in DLB and a corresponding decrement in cooperative interaction between working memory and secondary memory processes. Assessment of recognition memory span may contribute to the ability to distinguish between DLB and AD relatively early in the course of disease. Copyright © 2015. Published by Elsevier Ltd.
    Neuropsychologia 07/2015; 75. DOI:10.1016/j.neuropsychologia.2015.07.014 · 3.30 Impact Factor
  • Seung-Jae Lee · Eliezer Masliah ·

    Nature 06/2015; 522(7556). DOI:10.1038/nature14526 · 41.46 Impact Factor
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    ABSTRACT: Parkinson's disease (PD) is one of the most common causes of dementia and motor deficits in the elderly. PD is characterized by the abnormal accumulation of the synaptic protein alpha-synuclein (α-syn) and degeneration of dopaminergic neurons in substantia nigra, which leads to neurodegeneration and neuroinflammation. Currently, there are no disease modifying alternatives for PD; however, targeting neuroinflammation might be a viable option for reducing motor deficits and neurodegeneration. Lenalidomide is a thalidomide derivative designed for reduced toxicity and increased immunomodulatory properties. Lenalidomide has shown protective effects in an animal model of amyotrophic lateral sclerosis, and its mechanism of action involves modulation of cytokine production and inhibition of NF-κB signaling. In order to assess the effect of lenalidomide in an animal model of PD, mThy1-α-syn transgenic mice were treated with lenalidomide or the parent molecule thalidomide at 100 mg/kg for 4 weeks. Lenalidomide reduced motor behavioral deficits and ameliorated dopaminergic fiber loss in the striatum. This protective action was accompanied by a reduction in microgliosis both in striatum and hippocampus. Central expression of pro-inflammatory cytokines was diminished in lenalidomide-treated transgenic animals, together with reduction in NF-κB activation. These results support the therapeutic potential of lenalidomide for reducing maladaptive neuroinflammation in PD and related neuropathologies.
    Journal of Neuroinflammation 05/2015; 12(1):93. DOI:10.1186/s12974-015-0320-x · 5.41 Impact Factor
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    ABSTRACT: Background: Adult neurogenesis mirrors the brain´s endogenous capacity to generate new neurons throughout life. In the subventricular zone/ olfactory bulb system adult neurogenesis is linked to physiological olfactory function and has been shown to be impaired in murine models of neuronal alpha-Synuclein overexpression. We analyzed the degree and temporo-spatial dynamics of adult olfactory bulb neurogenesis in transgenic mice expressing human wild-type alpha-Synuclein (WTS) under the murine Thy1 (mThy1) promoter, a model known to have a particularly high tg expression associated with impaired olfaction. Results: Survival of newly generated neurons (NeuN-positive) in the olfactory bulb was unchanged in mThy1 transgenic animals. Due to decreased dopaminergic differentiation a reduction in new dopaminergic neurons within the olfactory bulb glomerular layer was present. This is in contrast to our previously published data on transgenic animals that express WTS under the control of the human platelet-derived growth factor β (PDGF) promoter, that display a widespread decrease in survival of newly generated neurons in regions of adult neurogenesis, resulting in a much more pronounced neurogenesis deficit. Temporal and quantitative expression analysis using immunofluorescence co-localization analysis and Western blots revealed that in comparison to PDGF transgenic animals, in mThy1 transgenic animals WTS is expressed from later stages of neuronal maturation only but at significantly higher levels both in the olfactory bulb and cortex. Conclusions: The dissociation between higher absolute expression levels of alpha-Synuclein but less severe impact on adult olfactory neurogenesis in mThy1 transgenic mice highlights the importance of temporal expression characteristics of alpha-Synuclein on the maturation of newborn neurons.
    PLoS ONE 05/2015; 10(5):e0126261. DOI:10.1371/journal.pone.0126261 · 3.23 Impact Factor
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    ABSTRACT: β-Amyloid (Aβ) accumulation in the brain is widely accepted to be critical to the development of Alzheimer's disease (AD). Current efforts at reducing toxic Aβ40 or 42 have largely focused on modulating γ-secretase activity to produce shorter, less toxic Aβ, while attempting to spare other secretase functions. In this paper we provide data that offer the potential for a new approach for the treatment of AD. The method is based on our previous findings that the production of Aβ from the interaction between the β-amyloid precursor protein (APP) and Presenilin (PS), as part of the γ-secretase complex, in cell culture is largely inhibited if the entire water-soluble NH2-terminal domain of PS is first added to the culture. Here we demonstrate that two small, non-overlapping water-soluble peptides from the PS-1 NH2-terminal domain can substantially and specifically inhibit the production of total Aβ as well as Aβ40 and 42 in vitro and in vivo in the brains of APP transgenic mice. These results suggest that the inhibitory activity of the entire amino terminal domain of PS-1 on Aβ production is largely focused in a few smaller sequences within that domain. Using biolayer interferometry and confocal microscopy we provide evidence that peptides effective in reducing Aβ give a strong, specific and biologically relevant binding with the purified ectodomain of APP 695. Finally, we demonstrate that the reduction of Aβ by the peptides does not affect the catalytic activities of β- or γ-secretase, or the level of APP. P4 and P8 are the first reported protein site-specific small peptides to reduce Aβ production in model systems of AD. These peptides and their derivatives offer new potential drug candidates for the treatment of AD.
    PLoS ONE 04/2015; 10(4):e0122451. DOI:10.1371/journal.pone.0122451 · 3.23 Impact Factor

Publication Stats

59k Citations
5,401.97 Total Impact Points


  • 1989-2015
    • University of California, San Diego
      • • Department of Medicine
      • • Department of Neurosciences
      • • Department of Pathology
      San Diego, California, United States
  • 2012
    • University of Pittsburgh
      • Department of Pathology
      Pittsburgh, Pennsylvania, United States
  • 2010
    • University of Southern California
      • Department of Medicine
      Los Angeles, CA, United States
  • 2009
    • University of California, Los Angeles
      • Department of Psychiatry and Biobehavioural Sciences
      Los Ángeles, California, United States
  • 2008
    • Weill Cornell Medical College
      New York, New York, United States
    • Drexel University
      Filadelfia, Pennsylvania, United States
  • 2006
    • University of California, Santa Barbara
      Santa Barbara, California, United States
  • 2005
    • University of Florence
      Florens, Tuscany, Italy
  • 2004
    • University of California, San Francisco
      San Francisco, California, United States
  • 2002
    • National University (California)
      San Diego, California, United States
    • The Ottawa Hospital
      Ottawa, Ontario, Canada
  • 1993-2002
    • The University of Tokyo
      • Department of Pharmaceutical Sciences
      白山, Tōkyō, Japan
  • 1990-2002
    • Kyoto University
      • • Institute for Chemical Research
      • • Department of Neurology
      Kyoto, Kyoto-fu, Japan
    • Massachusetts Institute of Technology
      Cambridge, Massachusetts, United States
  • 1997-2001
    • Naval Medical Center San Diego
      • Department of Pathology
      San Diego, California, United States
  • 1998-2000
    • University of San Diego
      San Diego, California, United States
  • 1994-1998
    • The Scripps Research Institute
      • Department of Molecular and Experimental Medicine
      La Jolla, California, United States
    • Brown University
      Providence, Rhode Island, United States
  • 1996
    • Whittier College
      • Chemistry
      Whittier, California, United States
  • 1995
    • Hungarian Academy of Sciences
      • MTA Institute of Experimental Medicine
      Budapeŝto, Budapest, Hungary
  • 1993-1994
    • Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
      Tlalpam, The Federal District, Mexico
  • 1992
    • Rutgers, The State University of New Jersey
      New Brunswick, New Jersey, United States