Eliezer Masliah

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

Are you Eliezer Masliah?

Claim your profile

Publications (859)5373.04 Total impact

  • [Show abstract] [Hide abstract]
    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
  • [Show abstract] [Hide abstract]
    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
    [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    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; DOI:10.1038/nm.3951 · 27.36 Impact Factor
  • [Show abstract] [Hide abstract]
    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
  • [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    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
  • [Show abstract] [Hide abstract]
    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; DOI:10.1001/jamaneurol.2015.1807
  • Eliezer Masliah · Brian Spencer
    [Show abstract] [Hide abstract]
    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
  • [Show abstract] [Hide abstract]
    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; DOI:10.1111/jnc.13253 · 4.28 Impact Factor
  • [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    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
  • [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case-control series. We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants. In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel-Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14-5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15-5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 × 10(-3)). The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.
    04/2015; 2(4):417-26. DOI:10.1002/acn3.185
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Tauopathies are a group of disorders leading to cognitive and behavioral impairment in the aging population. While four-repeat (4R) Tau is more abundant in corticobasal degeneration, progressive supranuclear palsy, and Alzheimer's disease, three-repeat (3R) Tau is the most abundant splice, in Pick's disease. A number of transgenic models expressing wild-type and mutant forms of the 4R Tau have been developed. However, few models of three-repeat Tau are available. A transgenic mouse model expressing three-repeat Tau was developed bearing the mutations associated with familial forms of Pick's disease (L266V and G272V mutations). Two lines expressing high (Line 13) and low (Line 2) levels of the three-repeat mutant Tau were analyzed. By Western blot, using antibodies specific to three-repeat Tau, Line 13 expressed 5-times more Tau than Line 2. The Tau expressed by these mice was most abundant in the frontal-temporal cortex and limbic system and was phosphorylated at residues detected by the PHF-1, AT8, CP9 and CP13 antibodies. The higher-expressing mice displayed hyperactivity, memory deficits in the water maze and alterations in the round beam. The behavioral deficits started at 6-8 months of age and were associated with a progressive increase in the accumulation of 3R Tau. By immunocytochemistry, mice from Line 13 displayed extensive accumulation of 3R Tau in neuronal cells bodies in the pyramidal neurons of the neocortex, CA1-3 regions, and dentate gyrus of the hippocampus. Aggregates in the granular cells had a globus appearance and mimic Pick's-like inclusions. There were abundant dystrophic neurites, astrogliosis and synapto-dendritic damage in the neocortex and hippocampus of the higher expresser line. The hippocampal lesions were moderately argyrophilic and Thioflavin-S negative. By electron microscopy, discrete straight filament aggregates were detected in some neurons in the hippocampus. This model holds promise for better understanding the natural history and progression of 3R tauopathies and their relationship with mitochondrial alterations and might be suitable for therapeutical testing.
    PLoS ONE 03/2015; 10(3):e0121570. DOI:10.1371/journal.pone.0121570 · 3.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Multiple system atrophy (MSA) is a neurodegenerative disease characterized by parkinsonism, ataxia and dysautonomia. Histopathologically, the hallmark of MSA is the abnormal accumulation of alpha-synuclein (α-syn) within oligodendroglial cells, leading to neuroinflammation, demyelination and neuronal death. Currently, there is no disease-modifying treatment for MSA. In this sense, we have previously shown that next-generation active vaccination technology with short peptides, AFFITOPEs®, was effective in two transgenic models of synucleinopathies at reducing behavioral deficits, α-syn accumulation and inflammation. In this manuscript, we used the most effective AFFITOPE® (AFF 1) for immunizing MBP-α-syn transgenic mice, a model of MSA that expresses α-syn in oligodendrocytes. Vaccination with AFF 1 resulted in the production of specific anti-α-syn antibodies that crossed into the central nervous system and recognized α-syn aggregates within glial cells. Active vaccination with AFF 1 resulted in decreased accumulation of α-syn, reduced demyelination in neocortex, striatum and corpus callosum, and reduced neurodegeneration. Clearance of α-syn involved activation of microglia and reduced spreading of α-syn to astroglial cells. This study further validates the efficacy of vaccination with AFFITOPEs® for ameliorating the neurodegenerative pathology in synucleinopathies.
    Molecular Neurodegeneration 03/2015; 10(1):10. DOI:10.1186/s13024-015-0008-9 · 6.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The relationship between primary age-related tauopathy (PART) and Alzheimer’s disease (AD) is currently a matter of discussion. Recently the term PART was referred to cases characterized by mainly allocortical neurofibrillary (NF) pathology (Braak stages 0-IV) with only few or no amyloid (Aβ) deposits (Thal Aβ phases 0-2) [49]. In addition, no elevated soluble Aβ was detected in this disorder [9, 46]. PART cases that lack any Aβ do not meet formal criteria for sporadic AD according to the NIA-AA guidelines [35]. These neurofibrillary tangle (NFT)+/Aβ-brains are commonly observed in extreme old age [9, 15, 19]. When associated with a high density of NFTs in the same distribution and some cognitive deficits, the disorder has been referred to as tangle-predominant senile dementia (TPSD) [27] or “tangle-only dementia” [55].The new neuropathologic criteria recommend subdividing PART cases into “definite” (Braak stage ≤IV, Thal Aβ phase 0) and “possible” (Braak stage ≤IV, Thal Aβ phase 1-2) ...
    Acta Neuropathologica 03/2015; 129(5). DOI:10.1007/s00401-015-1407-2 · 10.76 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The advent of more effective antiretroviral therapies has reduced the frequency of HIV dementia, however the prevalence of milder HIV associated neurocognitive disorders [HAND] is actually rising. Neurodegenerative mechanisms in HAND might include toxicity by secreted HIV-1 proteins such as Tat, gp120 and Nef that could activate neuro-inflammatory pathways, block autophagy, promote excitotoxicity, oxidative stress, mitochondrial dysfunction and dysregulation of signaling pathways. Recent studies have shown that Tat could interfere with several signal transduction mechanisms involved in cytoskeletal regulation, cell survival and cell cycle re-entry. Among them, Tat has been shown to hyper-activate cyclin-dependent kinase [CDK] 5, a member of the Ser/Thr CDKs involved in cell migration, angiogenesis, neurogenesis and synaptic plasticity. CDK5 is activated by binding to its regulatory subunit, p35 or p39. For this manuscript we review evidence showing that Tat, via calcium dysregulation, promotes calpain-1 cleavage of p35 to p25, which in turn hyper-activates CDK5 resulting in abnormal phosphorylation of downstream targets such as Tau, collapsin response mediator protein-2 [CRMP2], doublecoutin [DCX] and MEF2. We also present new data showing that Tat interferes with the trafficking of CDK5 between the nucleus and cytoplasm. This results in prolonged presence of CDK5 in the cytoplasm leading to accumulation of aberrantly phosphorylated cytoplasmic targets [eg: Tau, CRMP2, DCX] that impair neuronal function and eventually lead to cell death. Novel therapeutic approaches with compounds that block Tat mediated hyper-activation of CDK5 might be of value in the management of HAND.
    Current HIV Research 03/2015; 13(1). DOI:10.2174/1570162X13666150311164201 · 1.76 Impact Factor

Publication Stats

56k Citations
5,373.04 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
    • Konkuk University
      • School of Medicine
      Sŏul, Seoul, South Korea
  • 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
    • Laval University
      Quebec City, Quebec, Canada
  • 1997–2006
    • Naval Medical Center San Diego
      • Department of Pathology
      San Diego, California, United States
  • 2005
    • University of Florence
      Florens, Tuscany, Italy
  • 2004
    • University of California, San Francisco
      San Francisco, California, United States
  • 2002
    • The Ottawa Hospital
      Ottawa, Ontario, Canada
    • National University (California)
      San Diego, California, United States
  • 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
  • 1998–2000
    • University of San Diego
      San Diego, California, United States
  • 1999
    • University of Bologna
      Bolonia, Emilia-Romagna, Italy
  • 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