EARLY EVENTS IN ALZHEIMER PATHOGENESISSummaryPrincipal Investigator: SUE TILTON GRIFFIN Abstract: This Program has provided compelling evidence for a self amplifying cycle of interactions between neurons and glia, mediated largely by neuroinflammatory cytokines acting as drivers of Alzheimer's disease (AD) pathogenesis;chief among these is interleukin-1 (IL-1). We have focused on the entry points into this cycle, which is to say the early events in a given neuron's circuit of interactions with its local environs. Recent examinations of human tissue and of a newly acquired transgenic Alzheimer model indicate that pathology of the Alzheimer type is initially associated with neuronal elevation of apolipoprotein E (ApoE) and -amyloid precursor protein (APP). Empirical studies in cell culture suggest that the APP/ApoE response in tissue is due to a causal relationship in which APP expression is dependent on co-expression of ApoE, with ApoE e3 more efficacious than ApoE e4, and is modulated by IL-1. Neuronal APP elevation is accompanied by secretion of APP fragments, which activate microglia and cause glutamate release. Together, this suggests that a glutamate-ApoE-APP axis is initialized in the early neuronal responses to adverse stimuli and neuroinflammation. With these results, we were surprised to find that i) APP expression declines in neuronal somata as one approaches mature A plaques, either temporally or spatially;and ii) glial activation persists in Alzheimer brain in the presence or following "clearance" of A plaques. Together, these data inspire a hypothesis that unifies the current renewal of this Program: The typical acute-phase response of neurons to adverse stimuli is to elevate ApoE and APP expression via a coordinated, causal relationship between ApoE and APP expression that becomes uncoupled in AD pathogenesis, leaving neurons with insufficient APP and a propensity to make inappropriate cellular responses and to succumb to the excitotoxic stress perpetrated by "classical" activation of microglia. Human tissue and model systems will be used in Project 1 to identify and elucidate the basic elements of the glutamate-ApoE-APP axis, and the role of IL-1 in its failure in AD. Project 2 will identify, in two unique populations, common pathways for microglial activation and cytokine release and the degree to which this activation is reflected in mRNA and protein expression profiles. Project 3 will investigate key aspects of microglial activation related to oxidative production of glutamate and the differential modulation of this activation by IL-1a gene polymorphisms. Three cores provide administrative coordination (Core A), tissue banking and processing (Core B), and molecular/biochemical sample analyses (Core C) for these studies. The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. Funding Period: 1997-08-01 - 2015-03-31 more information: NIH RePORT Top Publications
Research Grants
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Publications
PKCδ/midkine pathway drives hypoxia-induced proliferation and differentiation of human lung epithelial cellsHanying Zhang
Department of Animal Sciences, University of Wyoming, Laramie, Wyoming
Am J Physiol Cell Physiol 306:C648-58. 2014..Manipulation of PKCδ and MK activity in epithelial cells might be beneficial for the treatment of hypoxia-mediated lung diseases. ..- Generation of reactive oxygen species in 1-methyl-4-phenylpyridinium (MPP+) treated dopaminergic neurons occurs as an NADPH oxidase-dependent two-wave cascadeW Michael Zawada
Donald W, Reynolds Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
J Neuroinflammation 8:129. 2011.... - Overexpression of serine racemase in retina and overproduction of D-serine in eyes of streptozotocin-induced diabetic retinopathyHaiyan Jiang
School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical College, 270 Xueyuan Road, Wenzhou, Zhejiang 325003, P R China
J Neuroinflammation 8:119. 2011..We tested possibility that SR and its product, D-serine, were altered in a rat model of DR... 
Striatal Aβ peptide deposition mirrors dementia and differentiates DLB and PDD from other parkinsonian syndromesM E Kalaitzakis
Neuropathology Unit, Centre for Neuroscience, Division of Experimental Medicine, Department of Medicine, Imperial College London, Charing Cross Campus, St Dunstan s Road, London, UK
Neurobiol Dis 41:377-84. 2011..More detailed examination of the morphology of the Aβ pathology suggests that it is the presence of cored amyloid plaques in DLB, but not PDD, that underlies the differences seen in PET imaging...- Capillary cerebral amyloid angiopathy identifies a distinct APOE epsilon4-associated subtype of sporadic Alzheimer's diseaseDietmar Rudolf Thal
Institute of Pathology, University of Ulm, Albert Einstein Allee 11, Ulm, Germany
Acta Neuropathol 120:169-83. 2010.... - Genetic loss of D-amino acid oxidase activity reverses schizophrenia-like phenotypes in miceV Labrie
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
Genes Brain Behav 9:11-25. 2010..Diminished DAO activity and elevations in D-serine may serve as an effective therapeutic intervention for the treatment of psychiatric symptoms... - Neuropathology and the neuroinflammation ideaRobert E Mrak
Department of Pathology, 2280 Dowling Hall, University of Toledo Health Science Campus MS 1090, 3000 Arlington Avenue, Toledo, OH 43614, USA
J Alzheimers Dis 18:473-81. 2009..Further observations have extended these ideas to alpha-synuclein-based diseases (Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy) as well as other neurodegenerative diseases and conditions... - Clinical correlates of pathology in the claustrum in Parkinson's disease and dementia with Lewy bodiesM E Kalaitzakis
Department of Clinical Neuroscience, Neuropathology Unit, Division of Neuroscience and Mental Health, Imperial College Healthcare NHS Trust, London, UK
Neurosci Lett 461:12-5. 2009..13 and 0.1, respectively). We demonstrate that pathology in the claustrum, a region of largely obscure physiological function, strongly relates to the presence of dementia in Parkinson's disease and DLB... - Serine racemase is associated with schizophrenia susceptibility in humans and in a mouse modelViviane Labrie
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
Hum Mol Genet 18:3227-43. 2009..Furthermore, analysis of SRR genetic variants in humans identified a robust association with schizophrenia. This study demonstrates that aberrant Srr function and diminished d-serine may contribute to schizophrenia pathogenesis... - Unique aspects of transcriptional regulation in neurons--nuances in NFkappaB and Sp1-related factorsXianrong R Mao
Department of Anesthesiology, Washington University School of Medicine, St Louis, MO 63110, USA
J Neuroinflammation 6:16. 2009..These findings and their implications for neuronal differentiation--as well as potential dedifferentiation during degenerative processes--are discussed here... - Paradoxical roles of serine racemase and D-serine in the G93A mSOD1 mouse model of amyotrophic lateral sclerosisMisty Thompson
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
J Neurochem 120:598-610. 2012.... - Roles of quaternary structure and cysteine residues in the activity of human serine racemaseWei Wang
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
BMC Biochem 12:63. 2011..Regulation of SR activity is still poorly understood. As step toward developing reagents and methods for investigating SR in vitro, we analyzed structure-function relationships of a recombinant enzyme of human sequence... - Apolipoprotein E expression is elevated by interleukin 1 and other interleukin 1-induced factorsLing Liu
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
J Neuroinflammation 8:175. 2011..These stressors include interleukin-1 (IL-1)-mediated neuroinflammation and glutamate-mediated excitotoxicity. Such circumstances are especially powerful when they transpire in the context of an APOE ε4 allele... - Down's syndrome, neuroinflammation, and Alzheimer neuropathogenesisDonna M Wilcock
Department of Physiology, Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA
J Neuroinflammation 10:84. 2013..the brains of fetuses, neonates, and children with DS opened the possibility that early events in Alzheimer pathogenesis were driven by cytokines... - Nox4-generated superoxide drives angiotensin II-induced neural stem cell proliferationElena Topchiy
Department of Behavioral Neuroscience, Oregon Health and Sciences University, 3181 SW Sam Jackson Park Rd, Mail Code L470, Portland, OR 97239, USA
Dev Neurosci 35:293-305. 2013.... - Disturbed sleep in Parkinson's disease: anatomical and pathological correlatesM E Kalaitzakis
Neuropathology Unit, Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK
Neuropathol Appl Neurobiol 39:644-53. 2013..g. restless legs syndrome and rapid eye movement sleep behaviour disorder). However, the exact pathological basis of disturbed sleep remains as yet undefined... - Review: microglia in protein aggregation disorders: friend or foe?S M Gentleman
Neuropathology Unit, Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK
Neuropathol Appl Neurobiol 39:45-50. 2013..A better understanding of their varied roles is essential if they are to be the target for novel therapeutic strategies... - A polymorphism in the upstream regulatory region of the interleukin-1α gene confers differential binding by transcription factors of the AP-1 familyAndrea M Moerman-Herzog
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States
Life Sci 90:975-9. 2012..We sought to determine the differential abilities of C- and T- containing versions of the -889 sequence to bind nuclear proteins from microglia... - Apolipoprotein epsilon 3 alleles are associated with indicators of neuronal resilienceOrwa Aboud
Donald W, Reynolds Department of Geriatrics, Reynolds Institute on Aging, 629 Jack Stephens Drive, Little Rock, AR 72205, USA
BMC Med 10:35. 2012.... - Cross-linking of serine racemase dimer by reactive oxygen species and reactive nitrogen speciesWei Wang
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
J Neurosci Res 90:1218-29. 2012..These findings suggest a compensatory feedback in which the consequences of neuroinflammation might dampen D-serine production to limit excitotoxic stimulation of NMDA receptors... - Muscle expression of genes associated with inflammation, growth, and remodeling is strongly correlated in older adults with resistance training outcomesRichard A Dennis
Geriatric Reasearch, Education, and Clinical Center, Central Arkansas Veterans Healthcare System, No Little Rock, Arkansas 72114 1706, USA
Physiol Genomics 38:169-75. 2009..These genes hold promise as useful predictors of training outcomes that could be used to design more effective exercise regimens for maintaining muscle function in older adults... - Alzheimer-type neuropathological changes in morbidly obese elderly individualsR E Mrak
Department of Pathology, University of Toledo College of Medicine, 3000 Arlington Avenue, Toledo, OH 43614, USA
Clin Neuropathol 28:40-5. 2009..Middle age obesity increases risk for Alzheimer disease (AD). This study evaluated neuropathological changes in morbidly obese patients ranging in age from 21-70 years... - Genetic inactivation of D-amino acid oxidase enhances extinction and reversal learning in miceViviane Labrie
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto M5G 1X5, Canada
Learn Mem 16:28-37. 2009..The NMDAR glycine site and DAO may be promising therapeutic targets to improve cognitive flexibility and inhibitory learning in psychiatric disorders such as schizophrenia and anxiety syndromes... - Association of the glutathione S-transferase omega-1 Ala140Asp polymorphism with cerebrovascular atherosclerosis and plaque-associated interleukin-1 alpha expressionHeike Kolsch
Stroke 38:2847-50. 2007..The objective of this study is to address the question of whether common vessel disorders known to cause vascular dementia are modified in their severity by this polymorphism... - Induction of serine racemase expression and D-serine release from microglia by secreted amyloid precursor protein (sAPP)Shengzhou Wu
Department of Neurology, Washington University School of Medicine, St Louis, MO, USA
Curr Alzheimer Res 4:243-51. 2007..D-serine may cooperate with glutamate to link neuroinflammation with excitotoxicity, suggesting a pathogenic mechanism applicable to neuronal death in AD and other neurodegenerative diseases... - Glutamate release from activated microglia requires the oxidative burst and lipid peroxidationSteven W Barger
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
J Neurochem 101:1205-13. 2007..Indeed, some of the neuroprotective effects of antioxidants may be due to interference with these events rather than direct protection against neuronal oxidation... - Alterations in presenilin 1 processing by amyloid-beta peptide in the rat retinaHelena R Watts
Department of Cellular and Molecular Neuroscience, Division of Neuroscience and Mental Health, Faculty of Medicine, Imperial College London, Charing Cross Campus, Fulham Palace Road, London, W6 8RF, UK
Exp Brain Res 181:69-77. 2007..These results suggest an A beta(1-42)-induced potentiation of a non-specific stress-related but inflammation-independent alteration of processing of PS1 in this in vivo model... - Glutamate receptor activation evokes calpain-mediated degradation of Sp3 and Sp4, the prominent Sp-family transcription factors in neuronsXianrong Mao
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
J Neurochem 100:1300-14. 2007..These data provide details of an impact of glutamate-receptor activation on molecular events connected to gene expression... - Glycogen synthase kinase-3 in neurodegeneration and neuroprotection: lessons from lithiumSaeed Yadranji Aghdam
School of Biology, University of Tehran, Tehran 14155 6455, Iran
Curr Alzheimer Res 4:21-31. 2007.... - Differential transcriptional control of the superoxide dismutase-2 kappaB element in neurons and astrocytesXianrong Mao
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA
J Biol Chem 281:35863-72. 2006.... - Pioglitazone induces apoptosis of macrophages in human adipose tissueAngela M Bodles
The Central Arkansas Veterans Healthcare System, and the Department of Medicine, Division of Endocrinology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
J Lipid Res 47:2080-8. 2006.... - Interleukin-1 mediates Alzheimer and Lewy body pathologiesW Sue T Griffin
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA
J Neuroinflammation 3:5. 2006..Glial activation, with overexpression of interleukin-1 (IL-1) and other proinflammatory cytokines, has been increasingly implicated in the pathogenesis of both AD and PD... - Inflammation and neurodegenerative diseasesW Sue T Griffin
Donald W Reynolds Department of Geriatrics, The University of Arkansas for Medical Sciences, and the Geriatric Research Education Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA
Am J Clin Nutr 83:470S-474S. 2006..Over a period of years, this slow, smoldering inflammation in the brain destroys sufficient neurons to cause the clinical signs of Alzheimer disease... - Common inflammatory mechanisms in Lewy body disease and Alzheimer diseaseRobert E Mrak
Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
J Neuropathol Exp Neurol 66:683-6. 2007..These neuroinflammatory processes may be a common link driving progression in both diseases and explaining the frequent overlap between the 2 diseases... - The dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson's disease: a critical analysis of alpha-synuclein stagingM E Kalaitzakis
University Department of Neuropathology, Division of Neuroscience and Mental Health, Imperial College London, Hammersmith Hospitals Trust, London, UK
Neuropathol Appl Neurobiol 34:284-95. 2008..However, the reliability of this stereotypical spread of alpha Syn pathology has been questioned. In addition, the comparative occurrence of alpha Syn pathology in the spinal cord and brain has not been closely studied... - Glial expression of cannabinoid CB(2) receptors and fatty acid amide hydrolase are beta amyloid-linked events in Down's syndromeE Nunez
Laboratorio de Apoyo a la Investigacion, Fundacion Hospital Alcorcon, 28922 Alcorcon, Madrid, Spain
Neuroscience 151:104-10. 2008..In addition, they confirm a striking differential pattern of distribution of FAAH and CB(2) receptors... - Acute and chronic effects of intravitreally injected beta-amyloid on the neurotransmitter system in the retinaOkezie I Aruoma
Department of Pharmaceutical and Biomedical Sciences, Touro College of Pharmacy, New York, NY 10027, USA
Toxicology 256:92-100. 2009.... - Relationships between expression of apolipoprotein E and beta-amyloid precursor protein are altered in proximity to Alzheimer beta-amyloid plaques: potential explanations from cell culture studiesSteven W Barger
Department of Geriatrics, Geriatric Research Education and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA
J Neuropathol Exp Neurol 67:773-83. 2008.... - Parenchymal and vascular Abeta-deposition and its effects on the degeneration of neurons and cognition in Alzheimer's diseaseDietmar Rudolf Thal
Institute of Pathology Laboratory of Neuropathology University of Ulm, Ulm, Germany
J Cell Mol Med 12:1848-62. 2008..Therefore, it seems to be necessary to protect the brain from Abeta-toxicity already in stages of the disease with minor neuron loss before the onset of cognitive symptoms... - Dementia and visual hallucinations associated with limbic pathology in Parkinson's diseaseM E Kalaitzakis
Department of Clinical Neuroscience, Neuropathology Unit, Division of Neuroscience and Mental Health, Imperial College Healthcare NHS Trust, London, UK
Parkinsonism Relat Disord 15:196-204. 2009..We conclude that alphaSyn in limbic regions is related to dementia in PD as well as to visual hallucinations when there is an underlying dementia... - Interactions between APP secretases and inflammatory mediatorsMagdalena Sastre
Division of Neuroscience and Mental Health, Imperial College London, The Hammersmith Hospital, Du Cane Road, London W12 0NN, UK
J Neuroinflammation 5:25. 2008..In this review we will discuss some of these issues and the role of the secretases in inflammation, independent of their effect on Abeta formation... - Sca-1-expressing nonmyogenic cells contribute to fibrosis in aged skeletal muscleMats Hidestrand
College of Health Sciences, University of Kentucky, 900 S Limestone, CTW 105, Lexington, KY 40536 0200, USA
J Gerontol A Biol Sci Med Sci 63:566-79. 2008..Thus, with age, a subset of myoblasts takes on an altered phenotype, which is marked by high Sca-1 expression. These cells do not participate in muscle regeneration, and instead may contribute to muscle fibrosis in aged muscle... - Cerebral amyloid angiopathy and its relationship to Alzheimer's diseaseDietmar Rudolf Thal
Laboratory of Neuropathology, Institute of Pathology, University of Ulm, Albert Einstein Allee 7, 89081 Ulm, Germany
Acta Neuropathol 115:599-609. 2008..Thus, blood flow alterations with subsequent hypoperfusion induced by CAA-related capillary occlusion presumably point to a second mechanism in which A beta adversely affects the brain in AD in addition to its direct neurotoxic effects... - Striatal beta-amyloid deposition in Parkinson disease with dementiaMichail E Kalaitzakis
University Department of Neuropathology, Division of Neuroscience and Mental Health, Imperial College London, Hammersmith Hospitals Trust, London, UK
J Neuropathol Exp Neurol 67:155-61. 2008..Striatal Abeta deposition was type-independent of Alzheimer disease changes in the cortex and was minimal in nondemented PD cases. We conclude that Abeta deposition in the striatum strongly correlates with dementia in PD... - Perispinal etanercept: potential as an Alzheimer therapeuticW Sue T Griffin
Geriatric Research, Education and Clinical Center, Neurobiology, Physiology, and Psychiatry, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA
J Neuroinflammation 5:3. 2008.... - Aging alters gene expression of growth and remodeling factors in human skeletal muscle both at rest and in response to acute resistance exerciseRichard A Dennis
Central Arkansas Veterans Healthcare System, North Little Rock GRECC, 2200 Fort Roots Dr Bldg 170, 3J 157, North Little Rock, AR 72114 1706, USA
Physiol Genomics 32:393-400. 2008..Future studies must determine the functional importance of these gene expression changes to protein synthesis, satellite cell activity, and other processes that are directly involved in the mechanisms of muscle hypertrophy... - Aging alters macrophage properties in human skeletal muscle both at rest and in response to acute resistance exerciseBeata Przybyla
Department of Geriatrics, University of Arkansas for Medical Sciences, 4301 West Markham 807, Little Rock, AR 72205, USA
Exp Gerontol 41:320-7. 2006..These findings suggest that aging results in a defective regulation of muscle macrophage function, both at baseline and in response to resistance exercise, that may limit muscle hypertrophy in older adults...
Research Grants
- Alerations of Sleep and Circadian Timing in AgingEve Van Cauter; Fiscal Year: 2013..Core B (Methods and Analysis) will standard operating procedures for data collection, archival and analysis. Core C will assay peripheral levels of hormones, cytokines and other blood constituents. ..