Jack H Jhamandas

University of Alberta, Edmonton, Alberta, Canada

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Publications (117)409.58 Total impact

  • Wen Fu, Diya Shi, David Westaway, Jack H Jhamandas
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    ABSTRACT: Alzheimer's disease (AD) is characterized neuropathologically by synaptic disruption, neuronal loss and deposition of amyloid beta (Aβ) protein in brain structures that are critical for memory and cognition. There is increasing appreciation, however, that astrocytes, which are the major non-neuronal glial cells, may play an important role in AD pathogenesis. Unlike neurons, astrocytes are resistant to Aβ cytotoxicity, which may in part be related to their greater reliance on glycolytic metabolism. Herein we show that in cultures of human fetal astrocytes, pharmacological inhibition or molecular down-regulation of a main enzymatic regulator of glycolysis, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB3), results in increased accumulation of Aβ within and around astrocytes and greater vulnerability of these cells to Aβ toxicity. We further investigated age-dependent changes in PFKFB3 and astrocytes in AD transgenic mice (TgCRND8) that over-express human Aβ. Using a combination of Western blotting and immunohistochemistry, we identified an increase in glial fibrillary acidic protein (GFAP) expression in astrocytes that paralleled escalation of Aβ plaque burden in TgCRND8 mice in an age-dependent manner. Furthermore, PFKFB3 expression also demonstrated an increase in these mice, albeit at a later age (9 months) than GFAP and Aβ. Immunohistochemical staining showed significant reactive astrogliosis surrounding Aβ plaques with increased PFKFB3 activity in 12-month old TgCRND8 mice, when AD pathology and behavioural deficits are fully manifest. These studies shed important light on the unique bioenergetic mechanisms within astrocytes that may contribute to the development of AD pathology. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 03/2015; 290(20). DOI:10.1074/jbc.M114.618157 · 4.60 Impact Factor
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    ABSTRACT: Accumulation of β-amyloid (Aβ) protein within the brain is a neuropathological hallmark of Alzheimer's disease (AD). One strategy to facilitate Aβ clearance from the brain is to promote Aβ catabolism. Matrix metalloproteinase-9 (MMP-9), a member of the family of Zn(+2)-containing endoproteases, known to be expressed and secreted by astrocytes, is capable of degrading Aβ. Histamine, a major aminergic brain neurotransmitter, stimulates the production of MMP-9 in keratinocytes through the histamine H1 receptor (H1R). In the present study, we show that histamine evokes a concentration- and calcium-dependent release of MMP-9 from human astrocytic U373 cells and primary cultures of human and rat astrocytes through the H1R subtype. Activation of H1R on astrocytes elevated intracellular levels of Ca(2+) that was accompanied by time-dependent increases in MAP kinase p44/p42 and PKC. In-cell western blots revealed dose-dependent increases in both enzymes, confirming involvement of these signal transduction pathways. We next investigated the extent of recombinant human MMP-9 (rhMMP-9) proteolytic activity on soluble oligomeric Aβ (soAβ). Mass spectrometry demonstrated time-dependent cleavage of soAβ (20 μM), but not another amyloidogenic protein amylin, upon incubation with rhMMP-9 (100 nM) at 1, 4 and 17 h. Furthermore, Western blots showed a shift in soAβ equilibrium toward lower order, less toxic monomeric species. In conclusion, both MAPK p44/p42 and PKC pathways appear to be involved in histamine-upregulated MMP-9 release via H1Rs in astrocytes. Furthermore, MMP-9 appears to cleave soAβ into less toxic monomeric species. Given the key role of histamine in MMP-9 release, this neurotransmitter may serve as a potential therapeutic target for AD.
    Brain Structure and Function 02/2015; DOI:10.1007/s00429-015-1007-x · 4.57 Impact Factor
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    ABSTRACT: Objective: We tested independent and interactive effects of Apolipoprotein E (ApoE) and pulse pressure (PP) concurrently and longitudinally across 9 years (3 waves) of episodic (EM) and semantic memory (SM) data from the Victoria Longitudinal Study. Method: We assembled a sample of older adults (n = 570, baseline M age = 71, age range = 53-95) and used latent growth modeling to test 4 research goals. Results: First, the best fitting memory model was 2 single latent variables for EM and SM, each exhibiting configural, metric, and partial scalar invariance. This model was analyzed as a parallel process model. Second, baseline level of PP predicted EM performance at centering age (75) and rate of 9-year EM change. Third, we observed no main effects of ApoE on EM or SM. Fourth, EM was affected by higher PP but differentially less so for carriers of the ApoE ε2 allele than the ε3 or ε4 alleles. Conclusions: PP is confirmed as a risk factor for concurrent and changing cognitive health in aging, but the effects operate differently across risk and protective allelic distribution of the ApoE gene. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
    Neuropsychology 12/2014; 29(3). DOI:10.1037/neu0000150 · 3.43 Impact Factor
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    ABSTRACT: Amyloid formation is the pathological hallmark of type 2 diabetes (T2D) and Alzheimer's disease (AD). These diseases are marked by extracellular amyloid deposits of islet amyloid polypeptide (IAPP) in the pancreas and amyloid β (Aβ) in the brain. Since IAPP may enter the brain and disparate amyloids can cross-seed each other to augment amyloid formation, we hypothesized that pancreatic derived IAPP may enter the brain to augment misfolding of Aβ in AD. The corollaries for validity of this hypothesis are that IAPP enters the brain, augments Aβ misfolding, [3] associates with Aβ plaques, and most importantly plasma levels correlate with AD diagnosis. We demonstrate the first 3 corollaries that: (1) IAPP is present in the brain in human cerebrospinal fluid (CSF), (2) synthetic IAPP promoted oligomerization of Aβ in vitro, and (3) endogenous IAPP localized to Aβ oligomers and plaques. For the 4th corollary, we did not observe correlation of peripheral IAPP levels with AD pathology in either an African American cohort or AD transgenic mice. In the African American cohort, with increased risk for both T2D and AD, peripheral IAPP levels were not significantly different in samples with no disease, T2D, AD, or both T2D and AD. In the Tg2576 AD mouse model, IAPP plasma levels were not significantly elevated at an age where the mice exhibit the glucose intolerance of pre-diabetes. Based on this negative data, it appears unlikely that peripheral IAPP cross-seeds or "infects" Aβ pathology in AD brain. However, we provide novel and additional data which demonstrate that IAPP protein is present in astrocytes in murine brain and secreted from primary cultured astrocytes. This preliminary report suggests a potential and novel association between brain derived IAPP and AD, however whether astrocytic derived IAPP cross-seeds Aβ in the brain requires further research.
    Current Alzheimer Research 11/2014; DOI:10.2174/1567205011666141107124538 · 3.80 Impact Factor
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    ABSTRACT: Research has reported associations among selected genetic susceptibility biomarkers and risk of (a) normal cognitive aging decrements, (b) established mild cognitive impairment (MCI), and (c) sporadic Alzheimer's disease (AD). In focusing on the transitional normal-to-early MCI phase, we examine associations among three theoretically relevant polymorphisms (APOE [rs429358, rs7412], BDNF [rs6265], COMT [rs4680]) and both baseline cognitive status (MCI vs. normal aging) and two-wave (four-year) longitudinal stability or change profiles. The latter included three profiles: (a) stable as normal aging, (b) stable or chronic impairment (MCI-to-MCI), and (c) emergence of impairment (normal-to-MCI).
    Frontiers in Aging Neuroscience 09/2014; 6:236. DOI:10.3389/fnagi.2014.00236 · 2.84 Impact Factor
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    ABSTRACT: Primary human fetal neurons and astrocytes (HFNs and HFAs, respectively) provide relevant cell types with which to study in vitro the mechanisms involved in various human neurological diseases, such as multiple sclerosis, Parkinson's disease, and Alzheimer's disease. However, the limited availability of human fetal cells poses a significant problem for the study of these diseases when a human cell model system is required. Thus, generating a readily available alternative cell source with the essential features of human neurons and astrocytes is necessary. The human teratoma-derived NTera2/D1 (NT2) cell line is a promising tool from which both neuronal and glial cells can be generated. Nevertheless, a direct comparison of NT2 neurons and primary HFNs in terms of their morphology physiological and chemical properties is still missing. This study directly compares NT2-derived neurons and primary HFNs using immunocytochemistry, confocal calcium imaging, high-performance liquid chromatography, and high-content analysis techniques. We investigated the morphological similarities and differences, levels of relevant amino acids, and internal calcium fluctuations in response to certain neurotransmitters/stimuli. We also compared NT2-derived astrocytes and HFAs. In most of the parameters tested, both neuronal and astrocytic cell types exhibited similarities to primary human fetal neurons and astrocytes. NT2-derived neurons and astrocytes are reliable in vitro tools and a renewable cell source that can serve as a valid alternative to HFNs/HFAs for mechanistic studies of neurological diseases. © 2014 Wiley Periodicals, Inc.
    Journal of Neuroscience Research 09/2014; 92(9). DOI:10.1002/jnr.23399 · 2.73 Impact Factor
  • Wen Fu, Jack H Jhamandas
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    ABSTRACT: Alzheimer's disease (AD) has historically been considered to arise due to the specific dysfunction and pathology of neurons in brain areas related to cognition. Recent progress indicates that astrocytes play an important role in neurodegenerative processes underlying AD. In this review, we focus on the different glucose metabolism profiles between astrocytes and neurons. In AD, a variety of CNS insults, such as the presence of amyloid protein, trigger reactive astrogliosis, which disrupts normal glycolytic activity in these cells. The compromise of the astrocytic metabolism in turn weakens the integrity of astrocytic-neuronal partnership, damages the normal brain homeostasis, impairs clearance of amyloid, promotes cytokine release and other inflammatory mediators, and over time, leads to neurodegeneration.
    Biogerontology 08/2014; DOI:10.1007/s10522-014-9525-0 · 3.01 Impact Factor
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    ABSTRACT: Background The human hypothalamus contains the neuropeptide FF (NPFF) neurochemical network. Animal experiments demonstrated that NPFF is implicated in the central cardiovascular regulation. We therefore studied expression of this peptide in the hypothalamus of individuals who suffered from essential hypertension (n = 8) and died suddenly due to acute myocardial infarction (AMI), and compared to that of healthy individuals (controls) (n = 6) who died abruptly due to mechanical trauma of the chest.Methods The frozen right part of the hypothalamus was cut coronally into serial sections of 20 μm thickness, and each tenth section was stained immunohistochemically using antibody against NPFF. The central section through each hypothalamic nucleus was characterized by the highest intensity of NPFF immunostaining and thus was chosen for quantitative densitometry.ResultsIn hypertensive patients, the area occupied by NPFF immunostained neuronal elements in the central sections through the suprachiasmatic nucleus (SCh), paraventricular hypothalamic nucleus (Pa), bed nucleus of the stria terminalis (BST), perinuclear zone (PNZ) of the supraoptic nucleus (SON), dorso- (DMH), ventromedial (VMH) nuclei, and perifornical nucleus (PeF) was dramatically decreased compared to controls, ranging about six times less in the VMH to 15 times less in the central part of the BST (BSTC). The NPFF innervation of both nonstained neuronal profiles and microvasculature was extremely poor in hypertensive patients compared to control.Conclusions The decreased NPFF expression in the hypothalamus of hypertensive patients might be a cause of impairment of its interaction with other neurochemical systems, and thereby might be involved in the pathogenesis of the disease.
    07/2014; 4(4). DOI:10.1002/brb3.229
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    ABSTRACT: Genetic polymorphisms of catechol-O-methyltransferase (COMT) and brain-derived neurotrophic factor (BDNF) have shown promising but inconsistent linkages with executive function (EF) in normal aging. We tested (1) independent contributions of COMT and BDNF risk; (2) potential magnification by risk-related interactions or additive effects with age; and (3) effect modification through stratification by apolipoprotein E (APOE) (risk: ε4+). Multiple linear regression models were applied with nondemented older adults (N = 634; range: 53-95 years) for an EF latent variable. No independent effects of BDNF or COMT on EF were observed. Additive (but not interactive) effects of COMT, BDNF, and age showed that older adults with a high-risk allelic combination performed differentially worse. Of 2 tested models of synergistic effects, the additive approach selectively supported a magnification hypothesis, which was qualified by the presence or the absence of APOE ε4.
    Neurobiology of Aging 06/2014; 36(1). DOI:10.1016/j.neurobiolaging.2014.06.020 · 4.85 Impact Factor
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    ABSTRACT: Objective: We report a gene × environment (health) study focusing on concurrent performance and longitudinal change in a latent-variable executive function (EF) phenotype. Specifically, we tested the independent and interactive effects of a recently identified insulin degrading enzyme genetic polymorphism (IDE rs6583817) and pulse pressure (PP; one prominent aging-related vascular health indicator) across up to 9 years of EF data in a sample of older adults from the Victoria Longitudinal Study. Both factors vary across a continuum of risk-elevating to risk-reducing and have been recently linked to normal and impaired cognitive aging. Method: We assembled a genotyped and typically aging group of older adults (n = 599, M age = 66 years at baseline), following them for up to 3 longitudinal waves (M interval = 4.4 years). We used confirmatory factor analyses, latent growth modeling, and path analyses to pursue 3 main research goals. Results: First, the EF single factor model was confirmed comprising 4 executive function tasks and it demonstrated measurement invariance across the waves. Second, older adults with the major IDE G allele exhibited better EF outcomes than homozygotes for the minor A allele at the centering age of 75 years. Adults with higher PP performed more poorly on EF tasks at age 75 years and exhibited greater EF longitudinal decline. Third, gene × health interaction analyses showed that worsening vascular health (higher PP) differentially affected EF performance in older adults with the IDE G allele. Conclusion: Genetic interaction analyses can reveal differential and magnifying effects on cognitive phenotypes in aging. In the present case, pulse pressure is confirmed as a risk factor for concurrent and changing cognitive health in aging, but the effects operate differently across the risk and protective allelic distribution of this IDE gene. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
    Psychology and Aging 03/2014; 29(2). DOI:10.1037/a0034656 · 2.73 Impact Factor
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    ABSTRACT: Widely expressed in the adult central nervous system, the cellular prion protein (PrP(C)) is implicated in a variety of processes including neuronal excitability. Dipeptidyl aminopeptidase-like protein 6 (DPP6) was first identified as a PrP(C) interactor using in vivo formaldehyde crosslinking of wild type (wt) mouse brain. This finding was confirmed in three cell lines and, as DPP6 directs the functional assembly of K(+) channels, we assessed the impact of wt and mutant PrP(C) upon Kv4.2-based cell-surface macromolecular complexes. Whereas a Gerstmann-Straussler-Scheinker (GSS) disease version of PrP with eight extra octarepeats was a loss-of-function both for complex formation and for modulation of Kv4.2 channels, wt PrP(C) - in a DPP6-dependent manner - modulated Kv4.2 channel properties causing an increase in peak amplitude, a rightward shift of the voltage-dependent steady-state inactivation curve, a slower inactivation and a faster recovery from steady-state inactivation. Thus the net impact of wt PrP(C) was one of enhancement, which plays a critical role in the down-regulation of neuronal membrane excitability and is associated with a decreased susceptibility to seizures. Insofar as previous work has established a requirement for wt PrP(C) in the Aβ-dependent modulation of excitability in cholinergic basal forebrain neurons, our findings implicate PrP(C) regulation of Kv4.2 channels as a mechanism contributing to the effects of oligomeric Aβ upon neuronal excitability and viability.
    Journal of Biological Chemistry 11/2013; 288(52). DOI:10.1074/jbc.M113.488650 · 4.60 Impact Factor
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    Wen Fu, Aarti Patel, Jack H Jhamandas
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    ABSTRACT: Amylin (islet amyloid polypeptide) and amyloid-beta (Aβ) protein, which are deposited within pancreatic islets of diabetics and brains of Alzheimer's patients respectively, share many biophysical and physiological properties. Emerging evidence indicates that the amylin receptor is a putative target receptor for the actions of human amylin and Aβ in the brain. The amylin receptor consists of the calcitonin receptor dimerized with a receptor activity-modifying protein and is widely distributed within central nervous system. Both amylin and Aβ directly activate this G protein-coupled receptor and trigger multiple common intracellular signal transduction pathways that can culminate in apoptotic cell death. Moreover, amylin receptor antagonists can block both the biological and neurotoxic effects of human amylin and Aβ. Amylin receptors thus appear to be involved in the pathophysiology of Alzheimer's disease and diabetes, and could serve as a molecular link between the two conditions that are associated epidemiologically.
    Frontiers in Aging Neuroscience 08/2013; 5:42. DOI:10.3389/fnagi.2013.00042 · 2.84 Impact Factor
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    ABSTRACT: Neurons and neighboring astrocytic glia are mostly studied in nervous tissues from rodents whereas less is known on their properties and interactions in human brain. Here, confocal/multiphoton fluorescence imaging for several hours revealed that co-cultured fetal human cortical neurons and astrocytes show pronounced spontaneous rises of cytosolic Ca(2+) which last for up to several minutes without concomitant changes in either movements or membrane potential of mitochondria. Similar Ca(2+) rises were evoked mainly in neurons by bath-applied glutamate or γ-aminobutyric acid (GABA) acting via NMDA+AMPA/Kainate and GABAA receptors, respectively. Predominantly in astrocytes, Ca(2+) baseline was elevated by adenosine-diphosphate (ADP) and adenosine triphosphate (ATP) acting via P2Y1 and P2X7 receptors likely causing release of glutamate and glutamine. Mainly astrocytes responded to histamine, whereas activation of muscarinic acetylcholine (ACh) receptors raised Ca(2+) in both cell types. Evoked neuronal and astrocytic Ca(2+) rises could last for several minutes without affecting mitochondrial movements or membrane potential. In contrast, reversible depolarization of mitochondrial membrane potential accompanied neuronal Ca(2+) rises induced by cyanide-evoked chemical anoxia or uncoupling of mitochondrial respiration with carbonyl-cyanide-4-(trifluoromethoxy)-phenylhydrazone (FCCP). During such metabolic perturbation, mitochondrial depolarization also occurred in astrocytes, whereas Ca(2+) was largely unaffected. In summary, fetal human cortical neurons and astrocytes show distinct patterns of neuro/glio-transmitter- and metabolically-evoked Ca(2+) rises and possess active mitochondria. One aspect of our discussion deals with the question of whether the functional mitochondria contribute to cellular Ca(2+) homeostasis that seems to be already well developed in fetal human cortical brain cells.
    Neuroscience 07/2013; 250. DOI:10.1016/j.neuroscience.2013.07.029 · 3.33 Impact Factor
  • Wen Fu, Jack H Jhamandas
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    ABSTRACT: Amylin (islet amyloid polypeptide) and amyloid beta protein (Ab), identified as proteinaceous deposits within the pancreas of diabetics and the brain of Alzheimer's patients respectively, share many biophysical, physiological and neurotoxic properties. Although no specific "Ab receptor" has been identified, emerging evidence suggests that the amylin receptor serves a putative target receptor for the actions of Ab in the brain. The amylin receptor consists of a calcitonin receptor dimerized with receptor activity-modifying proteins and is widely distributed within central nervous system. Ab can directly activate this G protein-coupled receptor and trigger multiple intracellular signal transduction messengers and pathways that include calcium, cAMP, ERK1/2 and Fos. Growing evidence suggests that amylin and amylin receptors are involved in many aspects of neurodegenerative pathophysiology. Developing therapeutic strategies aimed at modulating amylin receptor function may prove useful for treatment of neurodegenerative diseases such as Alzheimer's disease.
    Current Protein and Peptide Science 06/2013; DOI:10.2174/13892037113149990051 · 2.33 Impact Factor
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    ABSTRACT: We tested independent and interactive contributions of a recently noted and promising insulin degrading enzyme polymorphism (IDE; rs6583817) and type 2 diabetes (T2D) to executive function performance, concurrently and longitudinally. Regarding normal neurocognitive decline and Alzheimer's disease, T2D is a known risk factor and this IDE variant might contribute risk or risk reduction via the minor (A) or major (G) allele. We compared normal aging and T2D groups (baseline n =574; ages 53-95 years) over 2 longitudinal waves (mean interval = 4.4 years). We used confirmatory factor analysis, latent growth curve modeling, and path analysis. A confirmed single-factor model of 4 executive function tasks established the cognitive phenotype. This IDE variant predicted concurrent group differences and differential change in cognitive performance. Furthermore, the IDE major allele reduced risk of cognitive decline. T2D predicted performance only concurrently. Both IDE and T2D are associated with executive function levels in older adults, but only IDE moderated 2-wave change. Previously linked to Alzheimer's disease, this IDE variant should be further explored for its potential influence on cognitive phenotypes of normal aging.
    Neurobiology of aging 04/2013; 34(9). DOI:10.1016/j.neurobiolaging.2013.03.010 · 4.85 Impact Factor
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    Jack H Jhamandas, Valeri Goncharuk
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    ABSTRACT: Neuropeptide FF (NPFF) is an octapeptide belonging to the RFamide family of peptides that have been implicated in a wide variety of physiological functions in the brain including central cardiovascular and neuroendocrine regulation. The effects of these peptides are mediated via NPFF1 and NPFF2 receptors that are abundantly expressed in the rat and human brain. Herein, we review evidence for the role of NPFF in central regulation of blood pressure particularly within the brainstem and the hypothalamic paraventricular nucleus (PVN). At a cellular level, NPFF demonstrates distinct responses in magnocellular and parvocellular neurons of the PVN, which regulate the secretion of neurohypophyseal hormones and sympathetic outflow, respectively. Finally, the presence of NPFF system in the human brain and its alterations within the hypertensive brain are discussed.
    Frontiers in Endocrinology 02/2013; 4:8. DOI:10.3389/fendo.2013.00008
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    ABSTRACT: A key event in prion diseases is the conversion of the prion protein (PrP) from its native α-helical conformation to a misfolded, β-sheet rich conformation. Thus, preventing or reversing PrP misfolding could provide a means to disrupt prion disease progression and transmission. However, determining the structure of misfolded PrP has been notoriously difficult due to its inherent heterogeneity and aggregation behavior. For these reasons, simplified peptide fragments have been used as models that recapitulate characteristics of full-length PrP, such as amyloid-like aggregation and fibril formation, and in vitro toxicity. We provide a biochemical and structural comparison of PrP(127-147) peptides from elk, bovine and hamster using electrophysiology, electron microscopy and fluorescence. Our results demonstrate that the PrP(127-147) peptides adopt distinct populations of fibril structures. In addition, the elk PrP(127-147) peptide is unique in its ability to enhance Thioflavin T fluorescence and its ability to modulate neuronal ion channel conductances.
    Peptides 12/2012; 40. DOI:10.1016/j.peptides.2012.12.011 · 2.61 Impact Factor
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    ABSTRACT: Alzheimer's disease (AD) is characterized by accumulation of amyloid-β peptide (Aβ) in the brain regions that subserve memory and cognition. The amylin receptor is a potential target receptor for expression of the deleterious actions of soluble oligomeric Aβ species. We investigated whether the amylin receptor antagonist, AC253, neutralizes the depressant effects of Aβ(1-42) and human amylin on hippocampal long-term potentiation (LTP). Furthermore, we examined whether depressed levels of LTP observed in transgenic mice, which overexpress amyloid precursor protein (TgCRND8), could be restored with AC253. In mouse hippocampal brain slices, field EPSPs were recorded from the stratum radiatum layer of the CA1 area (cornu ammonis 1 region of the hippocampus) in response to electrical stimulation of Schaeffer collateral afferents. LTP was induced by 3-theta burst stimulation protocols. Aβ(1-42) (50 nm) and human amylin (50 nm), but not Aβ(42-1) (50 nm), depressed LTP evoked using both stimulation protocols. Preapplication of AC253 (250 nm) blocked Aβ- and human amylin-induced reduction of LTP without affecting baseline transmission or LTP on its own. In contrast to wild-type controls, where robust LTP is observed, 6- to 12-month-old TgCRND8 mice show blunted LTP that is significantly enhanced by application of AC253. Our data demonstrate that the effects of Aβ(1-42) and human amylin on LTP are expressed via the amylin receptor, and moreover, blockade of this receptor increases LTP in transgenic mice that show increased brain amyloid burden. Amylin receptor antagonists could serve as potentially useful therapeutic agents in AD.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 11/2012; 32(48):17401-6. DOI:10.1523/JNEUROSCI.3028-12.2012 · 6.75 Impact Factor
  • M Maulik, D Westaway, J H Jhamandas, S Kar
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    ABSTRACT: Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disorder believed to be initiated by accumulation of amyloid β (Aβ)-related peptides derived from proteolytic processing of amyloid precursor protein (APP). Research over the past two decades provided a mechanistic link between cholesterol and AD pathogenesis. Genetic polymorphisms in genes regulating the pivotal points in cholesterol metabolism have been suggested to enhance the risk of developing AD. Altered neuronal membrane cholesterol level and/or subcellular distribution have been implicated in aberrant formation, aggregation, toxicity, and degradation of Aβ-related peptides. However, the results are somewhat contradictory and we still do not have a complete understanding on how cholesterol can influence AD pathogenesis. In this review, we summarize our current understanding on the role of cholesterol in regulating the production/function of Aβ-related peptides and also examine the therapeutic potential of regulating cholesterol homeostasis in the treatment of AD pathology.
    Molecular Neurobiology 09/2012; 47(1). DOI:10.1007/s12035-012-8337-y · 5.29 Impact Factor
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    David Westaway, Jack H Jhamandas
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    ABSTRACT: Prion disease research has opened up the "black-box" of neurodegeneration, defining a key role for protein misfolding wherein a predominantly alpha-helical precursor protein, PrP (C) , is converted to a disease-associated, β-sheet enriched isoform called PrP (Sc) . In Alzheimer disease (AD) the Aβ peptide derived from the β-amyloid precuror protein APP folds in β-sheet amyloid. Early thoughts along the lines of overlap may have been on target, ( 1) but were eclipsed by a simultaneous (but now anachronistic) controversy over the role of PrP (Sc) in prion diseases. ( 2) (,) ( 3) Nonetheless, as prion diseases such as Creutzfeldt-Jakob Disease (CJD) are themselves rare and can include an overt infectious mode of transmission, and as familial prion diseases and familial AD involve different genes, an observer might reasonably have concluded that prion research could occasionally catalyze ideas in AD, but could never provide concrete overlaps at the mechanistic level. Surprisingly, albeit a decade or three down the road, several prion/AD commonalities can be found within the contemporary literature. One important prion/AD overlap concerns seeded spread of Aβ aggregates by intracerebral inoculation much like prions, ( 4) and, with a neuron-to-neuron 'spreading' also reported for pathologic forms of other misfolded proteins, Tau ( 5) (,) ( 6) and α-synuclein in the case of Parkinson Disease. ( 7) (,) ( 8) The concept of seeded spread has been discussed extensively elsewhere, sometimes under the rubric of "prionoids" ( 9) , and lies outside the scope of this particular review where we will focus upon PrP (C) . From this point the story can now be subdivided into four strands of investigation: (1) pathologic effects of Aβ can be mediated by binding to PrP (C) , ( 10) (2) the positioning of endoproteolytic processing events of APP by pathologic (β-cleavage + γ-cleavage) and non-pathologic (α-cleavage + γ-cleavage) secretase pathways is paralleled by seemingly analogous α- and β-like cleavage of PrP (C) (Fig. 1) (3) similar lipid raft environments for PrP (C) and APP processing machinery, ( 11) (-) ( 13) and perhaps in consequence, overlaps in repertoire of the PrP (C) and APP protein interactors ("interactomes"), ( 14) (,) ( 15) and (4) rare kindreds with mixed AD and prion pathologies. ( 16) Here we discuss confounds, consensus and conflict associated with parameters that apply to these experimental settings.
    Prion 09/2012; 6(4):359-63. DOI:10.4161/pri.20675 · 1.97 Impact Factor

Publication Stats

3k Citations
409.58 Total Impact Points

Institutions

  • 1990–2014
    • University of Alberta
      • • Division of Neurology
      • • Department of Medicine
      • • Centre for Neuroscience
      Edmonton, Alberta, Canada
  • 2007
    • The University of Calgary
      • Department of Clinical Neurosciences
      Calgary, Alberta, Canada
  • 2000
    • Memorial University of Newfoundland
      St. John's, Newfoundland and Labrador, Canada
  • 1989
    • McGill University
      Montréal, Quebec, Canada