Paul E Fraser

University of Toronto, Toronto, Ontario, Canada

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Publications (273)1668.03 Total impact

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    ABSTRACT: Mitochondrial morphology is regulated by fusion and fission machinery. Impaired mitochondria dynamics cause various diseases including Alzheimer's disease (AD). Appoptosin is a mitochondrial carrier protein located in the mitochondrial inner membrane. Appoptosin overexpression causes reactive oxygen species (ROS) overproduction and caspase-dependent apoptosis, while appoptosin downregulation abolishes β-amyloid-induced mitochondrial fragmentation and neuronal death in AD. Herein, we found that appoptosin overexpression resulted in mitochondrial fragmentation in a manner independent of its carrier function, ROS production, or caspase activation. Although appoptosin did not affect levels of mitochondrial outer-membrane fusion (MFN1 and MFN2), inner-membrane fusion (OPA1) and fission (DRP1 and FIS1) proteins, appoptosin interacted with MFN1 and MFN2, as well as the mitochondrial ubiquitin ligase MITOL but not OPA1, FIS1 or DRP1. Appoptosin overexpression impaired the interaction between MFN1 and MFN2 and mitochondrial fusion. On the other hand, co-expression of MFN1, MITOL and a dominant negative form of DRP1, DRP1(K38A) partially rescued appoptosin-induced mitochondrial fragmentation and apoptosis, whereas co-expression of FIS1 aggravated appoptosin-induced apoptosis. Together, our results demonstrate that appoptosin can interact with mitochondrial outer-membrane fusion proteins and regulates mitochondrial morphology.
    No preview · Article · Jan 2016 · Journal of Cell Science
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    ABSTRACT: Although trace levels of phosphorylated α-synuclein (α-syn) are detectable in normal brains, nearly all α-syn accumulated within Lewy bodies in Parkinson's disease brains is phosphorylated on serine 129 (S129). The role of the phosphoserine residue and its effects on α-syn structure, function, and intracellular accumulation are poorly understood. Here, co-expression of α-syn and polo-like kinase 2 (PLK2), a kinase that targets S129, was used to generate phosphorylated α-syn for biophysical and biological characterization. Misfolding and fibril formation of phosphorylated α-syn isoforms was detected earlier, though the fibrils remained phosphatase and protease sensitive. Membrane binding of α-syn monomers was differentially affected by phosphorylation depending on the PD-linked mutation. WT α-syn binding to presynaptic membranes was not affected by phosphorylation, whereas A30P α-syn binding was greatly increased and A53T α-syn was slightly lower, implicating distal effects of the carboxyl-terminal on amino-terminal membrane binding. Endocytic vesicle-mediated internalization of pre-formed fibrils into non-neuronal cells and dopaminergic neurons matched the efficacy of α-syn membrane binding. Lastly, the disruption of internalized vesicle membranes was enhanced by the phosphorylated α-syn isoforms, a potential means for misfolded extracellular or lumenal α-syn to access cytosolic α-syn. Our results suggest that the threshold for vesicle permeabilization is evident even at low levels of α-syn internalization, and are relevant to therapeutic strategies to reduce intercellular propagation of α-syn misfolding.
    Full-text · Article · Dec 2015 · Journal of Biological Chemistry
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    ABSTRACT: Background: IAPP1-37 and ProIAPP1-48 are amyloidogenic peptides implicated in β-cell death in diabetes. Interactions with metals may be involved in both the cytotoxicity of these peptides and their deposition as amyloids associated with diabetes-related pathologies. Methods: We have used the complementary methods of thioflavin T (ThT) fluorescence and transmission electron microscopy (TEM) to investigate the role of seeds and specifically metal-peptide seeds in accelerating amyloid formation by ProIAPP. In addition we have used these complementary methods alongside dynamic light scattering (DLS) to observe the dynamics of IAPP amyloid formation during the earliest phase of peptide aggregation. Results: Seeding universally resulted in an acceleration of amyloid formation, as indicated by increased ThT fluorescence, over the shorter term (minutes) while having no influence upon total amyloid deposits (no differences in ThT fluorescence) over many days. Only copper-peptide seeds were ineffective in accelerating amyloid formation above that observed for sham seeds (no peptide). Different seeding environments resulted in amyloid deposits of different fibrillar and non-fibrillar morphologies following longer term incubations regardless of the uniform nature of the respective measurements of ThT fluorescence. The aggregation dynamics of IAPP, mimicking its secretion into extracellular milieus, were complex and suggested that while metals at equimolar, generally increased rates of aggregation, with the possible exception of Cu(II), the range of sub-micron and micron-sized particles observed were not easily explained by either measurement of ThT fluorescence or imaging by TEM. Conclusions: Seeding may be significant in accelerating the formation of amyloid and in influencing the final morphologies of deposited amyloids but not in determining the total deposits of amyloid. It was of interest that copper-peptide seeds did not accelerate amyloid formation in the shorter term and this could indicate an incompatible seeding morphology due to copper? This first attempt to monitor aggregation dynamics of IAPP over only minutes has shown direct impact of metals on peptide particle size which could have implications for the cytotoxicity of IAPP in diabetes.
    Preview · Article · Dec 2015
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    ABSTRACT: Type 2 diabetes (T2DM), Alzheimer’s disease (AD), and insulin resistance are age-related conditions and increased prevalence is of public concern. Recent research has provided evidence that insulin resistance and impaired insulin signalling may be a contributory factor to the progression of diabetes, dementia, and other neurological disorders. Alzheimer’s disease (AD) is the most common subtype of dementia. Reduced release (for T2DM) and decreased action of insulin are central to the development and progression of both T2DM and AD. A literature search was conducted to identify molecular commonalities between obesity, diabetes, and AD. Insulin resistance affects many tissues and organs, either through impaired insulin signalling or through aberrant changes in both glucose and lipid (cholesterol and triacylglycerol) metabolism and concentrations in the blood. Although epidemiological and biological evidence has highlighted an increased incidence of cognitive decline and AD in patients with T2DM, the common molecular basis of cell and tissue dysfunction is rapidly gaining recognition. As a cause or consequence, the chronic inflammatory response and oxidative stress associated with T2DM, amyloid- β (A β ) protein accumulation, and mitochondrial dysfunction link T2DM and AD.
    Full-text · Article · Nov 2015 · Mediators of Inflammation
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    DESCRIPTION: Type 2 diabetes (T2DM), Alzheimer’s disease (AD), and insulin resistance are age-related conditions and increased prevalence is of public concern. Recent research has provided evidence that insulin resistance and impaired insulin signalling may be a contributory factor to the progression of diabetes, dementia, and other neurological disorders. Alzheimer’s disease (AD) is the most common subtype of dementia. Reduced release (for T2DM) and decreased action of insulin are central to the development and progression of both T2DM and AD. A literature search was conducted to identify molecular commonalities between obesity, diabetes, and AD. Insulin resistance affects many tissues and organs, either through impaired insulin signalling or through aberrant changes in both glucose and lipid (cholesterol and triacylglycerol) metabolism and concentrations in the blood. Although epidemiological and biological evidence has highlighted an increased incidence of cognitive decline and AD in patients with T2DM, the common molecular basis of cell and tissue dysfunction is rapidly gaining recognition. As a cause or consequence, the chronic inflammatory response and oxidative stress associated with T2DM, amyloid-β (Aβ) protein accumulation, and mitochondrial dysfunction link T2DM and AD.
    Full-text · Research · Nov 2015
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    ABSTRACT: Although the formation of beta-amyloid (Aβ) deposits in the brain is a hallmark of Alzheimer's Disease (AD), the soluble oligomers rather than the mature amyloid fibrils most likely contribute to Aβ toxicity and neurodegeneration. Thus, the discovery of agents targeting soluble (Aβ) oligomers is highly desirable for early diagnosis prior to the manifestation of a clinical AD phenotype and also more effective therapies. We have previously reported that a novel 15 a.a peptide (15mer), isolated via phage display screening, targeted Aβ and attenuated its neurotoxicity (1). The aim of the current study was to generate and biochemically characterise analogues of this peptide with improved stability and therapeutic potential. We demonstrated that a stable analogue of the 15 a.a. peptide (15M S.A.) retained the activity and potency of the parent peptide and demonstrated improved proteolytic resistance in vitro (stable to t=300min c.f. t=30min for the parent peptide). This candidate reduced the formation of soluble Aβ42 oligomers with the concurrent generation of non-toxic insoluble aggregates measuring up to 25-30 nm diameter as determined by atomic force microscopy. The 15M S.A. candidate directly interacted with oligomeric Aβ42, as shown by coimmunoprecipitation and Surface Plasmon Resonance/Biacore analysis, with an affinity in the low micromolar range. Furthermore, this peptide bound fibrillar Aβ42 and also stained plaques ex vivo in brain tissue from AD model mice. Given its multifaceted ability to target monomeric and aggregated Aβ42 species, this candidate holds promise for novel preclinical AD imaging and therapeutic strategies.
    Full-text · Article · Nov 2015 · Journal of Biological Chemistry
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    Full-text · Dataset · Nov 2015
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    ABSTRACT: The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary and sufficient for neurotoxicity in a C. elegans model of FUS-dependent neurodegeneration. They trap other ribonucleoprotein (RNP) granule components and disrupt RNP granule function. One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation. Nuclear FUS granules may be similarly affected. Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins.
    Full-text · Article · Oct 2015 · Neuron
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    ABSTRACT: The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary and sufficient for neurotoxicity in a C. elegans model of FUS-dependent neurodegeneration. They trap other ribonucleoprotein (RNP) granule components and disrupt RNP granule function. One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation. Nuclear FUS granules may be similarly affected. Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins.
    Full-text · Article · Oct 2015 · Neuron
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    Full-text · Article · Sep 2015
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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.
    Full-text · Article · Sep 2015 · Neuron
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    ABSTRACT: The ATP-binding cassette transporter A7 (ABCA7) has been identified as a susceptibility factor of late-onset Alzheimer's disease (LOAD) in Genome Wide Association Studies (GWAS). ABCA7 has been shown to mediate phagocytosis and affects membrane trafficking. The current study examines the impact of ABCA7 loss-offunction on amyloid precursor protein (APP) processing and generation of amyloid-β (Aβ). Suppression of endogenous ABCA7 in several different cell lines resulted in increased β-secretase cleavage and elevated Aβ. ABCA7 knockout mice displayed an increased production of endogenous murine amyloid Aβ42 species. Crossing ABCA7 deficient animals to an APP transgenic model resulted in significant increases in the soluble Aβ as compared to mice expressing normal levels of ABCA7. Only modest changes in the amount of insoluble Aβ and amyloid plaque densities were observed once the amyloid pathology was well developed while Aβ deposition was enhanced in younger animals. In vitro studies indicated a more rapid endocytosis of APP in ABCA7 knockout cells that is mechanistically consistent with the increased Aβ production. These in vitro and in vivo findings indicate a direct role of ABCA7 in amyloid processing, which may be associated with its primary biological function to regulate endocytic pathways. Several potential loss-of-function ABCA7 mutations and deletions linked to AD have recently been identified which, in some instances, have a great impact than ApoE allelic variants. A reduction in ABCA7 expression or loss of function would be predicted to increase amyloid production and that may be a contributing factor in the associated AD susceptibility. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    No preview · Article · Aug 2015 · Journal of Biological Chemistry
  • N Wijesekara · R Ahrens · L Wu · K Ha · Y Liu · M B Wheeler · P E Fraser
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    ABSTRACT: Increasing evidence points to the cytotoxicity of islet amyloid polypeptide (IAPP) aggregates as a major contributor to the loss of beta cell mass in type 2 diabetes. Prevention of IAPP amyloid formation represents a potential treatment to increase beta cell survival and function. The IAPP inhibitory peptide, D-ANFLVH, had been previously shown to prevent islet amyloid accumulation in cultured human islets. To assess its activity in vivo, D-ANFLVH was administered by intraperitoneal injection into a human IAPP transgenic mouse model, which replicates type 2 diabetes islet amyloid pathology. The peptide was a potent inhibitor of islet amyloid deposition, resulting in reduced islet cell apoptosis and preservation of beta cell area leading to improved glucose tolerance. These findings provide support for a key role of islet amyloid in beta cell survival and validate the application of anti-amyloid compounds as therapeutic strategies to maintain normal insulin secretion in type 2 diabetes patients. This article is protected by copyright. All rights reserved.
    No preview · Article · Jun 2015 · Diabetes Obesity and Metabolism
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    ABSTRACT: Protein synthesis is crucial for the maintenance of long-term-memory-related synaptic plasticity. The prion-like cytoplasmic polyadenylation element-binding protein 3 (CPEB3) regulates the translation of several mRNAs important for long-term synaptic plasticity in the hippocampus. Here, we provide evidence that the prion-like aggregation and activity of CPEB3 is controlled by SUMOylation. In the basal state, CPEB3 is a repressor and is soluble. Under these circumstances, CPEB3 is SUMOylated in hippocampal neurons both in vitro and in vivo. Following neuronal stimulation, CPEB3 is converted into an active form that promotes the translation of target mRNAs, and this is associated with a decrease of SUMOylation and an increase of aggregation. A chimeric CPEB3 protein fused to SUMO cannot form aggregates and cannot activate the translation of target mRNAs. These findings suggest a model whereby SUMO regulates translation of mRNAs and structural synaptic plasticity by modulating the aggregation of the prion-like protein CPEB3. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Jun 2015 · Cell Reports
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    ABSTRACT: Small ubiquitin-like modifier-1 (SUMO1) plays a number of roles in cellular events and recent evidence has given momentum for its contributions to neuronal development and function. Here, we have generated a SUMO1 transgenic mouse model with exclusive overexpression in neurons in an effort to identify in vivo conjugation targets and the functional consequences of their SUMOylation. A high-expressing line was examined which displayed elevated levels of mono-SUMO1 and increased high molecular weight conjugates in all brain regions. Immunoprecipitation of SUMOylated proteins from total brain extract and proteomic analysis revealed ~95 candidate proteins from a variety of functional classes, including a number of synaptic and cytoskeletal proteins. SUMO1 modification of synaptotagmin-1 was found to be elevated as compared to non-transgenic mice. This observation was associated with an age-dependent reduction in basal synaptic transmission and impaired presynaptic function as shown by altered paired pulse facilitation, as well as a decrease in spine density. The changes in neuronal function and morphology were also associated with a specific impairment in learning and memory while other behavioral features remained unchanged. These findings point to a significant contribution of SUMO1 modification on neuronal function which may have implications for mechanisms involved in mental retardation and neurodegeneration.
    Full-text · Article · May 2015 · Scientific Reports
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    ABSTRACT: An expanded G4C2 repeat in C9orf72 represents the most common known genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the lower limit for pathological expansions is unknown (the suggested cutoff is 30 repeats). It has been proposed that the expansion might have occurred only once in human history and subsequently spread throughout the population. However, our present findings support a hypothesis of multiple origins for the expansion. We report a British-Canadian family in whom a ∼70-repeat allele from the father (unaffected by ALS or FTLD at age 89 years) expanded during parent-offspring transmission and started the first generation affected by ALS (four children carry an ∼1,750-repeat allele). Epigenetic and RNA-expression analyses further discriminated the offspring's large expansions (which were methylated and associated with reduced C9orf72 expression) from the ∼70-repeat allele (which was unmethylated and associated with upregulation of C9orf72). Moreover, RNA foci were only detected in fibroblasts from offspring with large expansions, but not in the father, who has the ∼70-repeat allele. All family members with expansions were found to have an ancient known risk haplotype, although it was inherited on a unique 5-Mb genetic backbone. We conclude that small expansions (e.g., 70 repeats) might be considered "pre-mutations" to reflect their propensity to expand in the next generation. Follow-up studies might help explain the high frequency of ALS- or FTLD-affected individuals with an expansion but without a familial history (e.g., 21% among Finnish ALS subjects). Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · May 2015 · The American Journal of Human Genetics
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    ABSTRACT: Islet transplantation is a promising therapy for patients with diabetes, but its long-term success is limited by many factors, including the formation of islet amyloid deposits. Heparin is employed in clinical islet transplantation to reduce clotting but also promotes fibrillization of amyloidogenic proteins. We hypothesized that heparin treatment of islets during pre-transplant culture may enhance amyloid formation leading to beta cell loss and graft dysfunction. Heparin promoted the fibrillization of human islet amyloid polypeptide (IAPP) and enhanced its toxicity to INS-1 beta cells. Heparin increased amyloid deposition in cultured human islets, but surprisingly decreased islet cell apoptosis. Treatment of human islets with heparin prior to transplantation increased the likelihood of graft failure. Removal of islet heparan sulfate glycosaminoglycans, which localize with islet amyloid deposits in type 2 diabetes, by heparinase treatment decreased amyloid deposition and protected against islet cell death. These findings raise the possibility that pretransplant treatment of human islets with heparin could potentiate IAPP aggregation and amyloid formation and may be detrimental to subsequent graft function. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.
    No preview · Article · Apr 2015 · American Journal of Transplantation
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    ABSTRACT: Inherited variants in multiple different genes are associated with increased risk for Alzheimer's disease (AD). In many of these genes, the inherited variants alter some aspect of the production or clearance of the neurotoxic amyloid β-peptide (Aβ). Thus missense, splice site or duplication mutants in the presenilin 1 (PS1), presenilin 2 (PS2) or the amyloid precursor protein (APP) genes, which alter the levels or shift the balance of Aβ produced, are associated with rare, highly penetrant autosomal dominant forms of Familial Alzheimer's Disease (FAD). Similarly, the more prevalent late-onset forms of AD are associated with both coding and non-coding variants in genes such as SORL1, PICALM and ABCA7 that affect the production and clearance of Aβ. This review summarises some of the recent molecular and structural work on the role of these genes and the proteins coded by them in the biology of Aβ. We also briefly outline how the emerging knowledge about the pathways involved in Aβ generation and clearance can be potentially targeted therapeutically. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Mar 2015 · Molecular and Cellular Neuroscience
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    ABSTRACT: The presenilin genes were first identified as the site of missense mutations causing early onset autosomal dominant familial Alzheimer's disease. Subsequent work has shown that the presenilin proteins are the catalytic subunits of a hetero-tetrameric complex containing APH1, nicastrin and PEN-2. This complex (variously termed presenilin complex or gamma-secretase complex) performs an unusual type of proteolysis in which the transmembrane domains of Type I proteins are cleaved within the hydrophobic compartment of the membrane. This review describes some of the molecular and structural biology of this unusual enzyme complex. The presenilin complex is a bilobed structure. The head domain contains the ectodomain of nicastrin. The base domain contains a central cavity with a lateral cleft that likely provides the route for access of the substrate to the catalytic cavity within the centre of the base domain. There are reciprocal allosteric interactions between various sites in the complex that affect its function. For instance, binding of Compound E, a peptidomimetic inhibitor to the PS1 N-terminus, induces significant conformational changes that reduces substrate binding at the initial substrate docking site, and thus inhibits substrate cleavage. However, there is a reciprocal allosteric interaction between these sites such that prior binding of the substrate to the initial docking site paradoxically increases the binding of the Compound E peptidomimetic inhibitor. Such reciprocal interactions are likely to form the basis of a gating mechanism that underlies access of substrate to the catalytic site. An increasingly detailed understanding of the structural biology of the presenilin complex is an essential step towards rational design of substrate- and/or cleavage site-specific modulators of presenilin complex function.
    Full-text · Article · Dec 2014 · Molecular Neurodegeneration
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    ABSTRACT: The pathogenesis of Alzheimer disease (AD) is characterized by the aggregation of amyloid-β (Aβ) peptides leading to deposition of senile plaques and a progressive decline of cognitive functions, which currently remains the main criterion for its diagnosis. Robust biomarkers for AD do not yet exist, although changes in the cerebrospinal fluid levels of tau and Aβ represent promising candidates in addition to brain imaging and genetic risk profiling. Although concentrations of soluble Aβ42 correlate with symptoms of AD, less is known about the biological activities of Aβ peptides which are generated from the amyloid-β protein precursor. An unbiased DNA microarray study showed that Aβ42, at sub-lethal concentrations, specifically increases expression of several genes in neuroblastoma cells, notably the insulin-like growth factor binding proteins 3 and 5 (IGFBP3/5), the transcription regulator inhibitor of DNA binding, and the transcription factor Lim only domain protein 4. Using qRT-PCR, we confirmed that mRNA levels of the identified candidate genes were exclusively increased by the potentially neurotoxic Aβ42 wild-type peptide, as both the less toxic Aβ40 and a non-toxic substitution peptide Aβ42 G33A did not affect mRNA levels. In vivo immunohistochemistry revealed a corresponding increase in both hippocampal and cortical IGFBP5 expression in an AD mouse model. Proteomic analyses of human AD cerebrospinal fluid displayed increased in vivo concentrations of IGFBPs. IGFBPs and transcription factors, as identified here, are modulated by soluble Aβ42 and may represent useful early biomarkers.
    Full-text · Article · Oct 2014 · Journal of Alzheimer's disease: JAD

Publication Stats

24k Citations
1,668.03 Total Impact Points

Institutions

  • 1992-2015
    • University of Toronto
      • • Department of Laboratory Medicine and Pathobiology
      • • Department of Medical Biophysics
      • • Tanz Centre for Research in Neurodegenerative Diseases
      • • Department of Medicine
      Toronto, Ontario, Canada
    • Harvard University
      Cambridge, Massachusetts, United States
    • Valley Children's Hospital
      Мадера, California, United States
  • 1997
    • Kingston General Hospital
      Kingston, Ontario, Canada
  • 1994
    • Università degli Studi di Torino
      Torino, Piedmont, Italy
  • 1993
    • Massachusetts Institute of Technology
      • Department of Chemistry
      Cambridge, Massachusetts, United States
  • 1991-1992
    • Harvard Medical School
      • Department of Neurology
      Boston, Massachusetts, United States