Characterization of an FAD pathogenic PS1 mutation with complete loss of activity

Summary

Principal Investigator: HANNAH LOUISE BRAUTIGAM
Abstract: DESCRIPTION (provided by applicant): The neuropathological hallmarks of Alzheimer's disease (AD) consist of extracellular amyloid plaques, amyloid angiopathy, neurofibrillary tangles, inflammation, dystrophic neurites, and neuronal death. Rare, autosomal dominant familial forms of AD (FAD) have provided us with most of what is currently known of the molecular basis of the disease. Most FAD cases result in mutations in a polytopic membrane protein, presenilin 1 (PS1), that contains the active site for the 3-secretase enzyme, and which, in turn, determines the carboxyl terminus of the amyloid beta peptide (A2). Most A2 peptides end at residue 40, but a minor quantity ends at residue 42 and are highly prone to aggregation. The amyloid hypothesis of AD suggests that this increase in A2-42/40 results in a cascade that ultimately leads to hyperphosphorylated tau, synaptic dysfunction, and neuronal death. When new FAD families are identified, routinely, the PS1 gene is sequenced, and if a PS1 mutation is the cause, then either missense or deletion mutations will be found in the DNA of affected but not unaffected family members. Such was the case of the Tasmanian (Tas-1) family. Kwok et al. (2003) described the pathology and the genetics of the Tas-1 family;the pathogenic mutation in Tas-1 is a missense mutation, L271V, which disrupts alternative splicing of the PS1 gene, and results in a gene that lacks exon 8 (PS1 8). The goal of the current project is to characterize this novel FAD pathogenic PS1 mutation. Based on the work of Kwok et al. (2003), the overall objectives and methods of the project will be to determine if PS1 8 is catalytically inactive. Preliminary data showed that crossing the PS1 8 mutation with a PS1 (-/-) knock-out (KO) mouse did not rescue the KO phenotype seen in PS1 (-/-) KO animals, as they are embryonic lethal. In the current proposal, behavioral deficits and levels of A2-42, A2-42/40, and A2 oligomers will be determined in PS1 8 mice crossed with a mouse model harboring a mutation in APP. Also, histological analyses will be utilized and APP cleavage will be determined in these mouse models. Finally, further to evaluate whether PS1 8 is a loss of function mutation and to distinguish between the older dimer model and the more recent 1:1:1:1 model of the 3-secretase complex, cell culture, co-immunoprecipitation, confocal microscopy, and alpha screen techniques will be employed to evaluate whether PS1 8 is interacting with wt PS1 resulting in 3-secretase's altered substrate cleavage. Resolving the function of this protein in vivo and in vitro will allow us to further understand the mechanisms underlying FAD and possibly elucidate PS1 as a putative target of therapeutic intervention for AD.
Funding Period: 2011-09-30 - 2014-09-29
more information: NIH RePORT

Top Publications

  1. pmc The isotropic fractionator provides evidence for differential loss of hippocampal neurons in two mouse models of Alzheimer's disease
    Hannah Brautigam
    Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
    Mol Neurodegener 7:58. 2012
  2. pmc Early fear memory defects are associated with altered synaptic plasticity and molecular architecture in the TgCRND8 Alzheimer's disease mouse model
    John W Steele
    Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, NY, 10065, USA Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
    J Comp Neurol 522:2319-35. 2014

Detail Information

Publications2

  1. pmc The isotropic fractionator provides evidence for differential loss of hippocampal neurons in two mouse models of Alzheimer's disease
    Hannah Brautigam
    Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
    Mol Neurodegener 7:58. 2012
    ..We investigated whether two APP mouse models characterized by different folding states of amyloid showed different neuronal densities using an accurate method of cell counting...
  2. pmc Early fear memory defects are associated with altered synaptic plasticity and molecular architecture in the TgCRND8 Alzheimer's disease mouse model
    John W Steele
    Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, NY, 10065, USA Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
    J Comp Neurol 522:2319-35. 2014
    ..These changes, taken together with toxic insults from amyloid-β protein, may underlie the observed neuronal loss...

Research Grants30

  1. Expanding the National Health Accounts
    David M Cutler; Fiscal Year: 2013
    ..Establishment of a set of national health accounts will allow us as a society to understand which medical interventions improve the health of the U.S. population most efficiently. ..
  2. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  3. Alzheimer's Disease Research Center at Columbia University
    Scott A Small; Fiscal Year: 2013
    ..HIPAA compliant data organization and statistical consulting services are provided under the ADRC to the research community at Columbia and external to it. ..
  4. Sleep/Wake Fragmentation with Age: Molecular Mechanisms
    ALLAN IAN PACK; Fiscal Year: 2013
    ..These three projects are supported by three cores;a) Administrative Core;b) Mouse Behavioral Core;and c) Biostatistics and Bioinformatics Core. ..
  5. PHYSIOLOGY OF BONE METABOLISM IN AN AGING POPULATION
    Sundeep Khosla; Fiscal Year: 2013
    ..Collectively, these studies strive to provide a comprehensive assesment of the pathogenesis and clinical impact of one of the most important disorders facing our aging population. ..
  6. ApoE Receptor Biology and Neurodegeneration
    Mary Jo Ladu; Fiscal Year: 2013
    ..This Program will thus provide new and valuable information about how apoE and apoE receptors affect the pathogenesis of Alzheimer's disease. ..
  7. Knockin Mouse Models of Alzheimers Disease
    Hui Zheng; Fiscal Year: 2013
    ....
  8. APP/AB/Tau biochemistry in transgenic mice, familial and sporadic AD
    Alex E Roher; Fiscal Year: 2013
    ..A more complete understanding of AD molecular phenotypes and their clinical responses will aid in the discovery and application of efficacious treatments that will prevent AD or enhance the quality of life of AD patients. ..
  9. Emory Alzheimer's Disease Center
    Allan I Levey; Fiscal Year: 2013
    ..abstract_text> ..
  10. Roles of reticulon proteins in neurodegenerative diseases
    Riqiang Yan; Fiscal Year: 2013
    ..abstract_text> ..
  11. Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration
    Jeffery W Kelly; Fiscal Year: 2013
    ..abstract_text> ..
  12. Presenilins and APP in Protein Trafficking
    Huaxi Xu; Fiscal Year: 2013
    ..Results of these studies will greatly facilitate our understanding of AD pathogenesis and aid in the development of therapeutics. ..
  13. Behaviors on Surveys and in the Economy: HRS and Beyond
    Robert J Willis; Fiscal Year: 2013
    ..abstract_text> ..
  14. Alerations of Sleep and Circadian Timing in Aging
    Eve 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. ..
  15. Alzheimer's Disease Research Center
    Oscar L Lopez; Fiscal Year: 2013
    ..Alzheimer's centers such as the one in Pittsburgh play a critical role in the nation's struggle to: 1) care for those currently afflicted;2) improve diagnosis and treatment;and 3) find a means of prevention. ..
  16. Wisconsin Alzheimer's Disease Research Center
    Sanjay Asthana; Fiscal Year: 2013
    ..abstract_text> ..
  17. ALZHEIMER DISEASE RESEARCH CENTER
    HELENA CHANG CHUI; Fiscal Year: 2013
    ..abstract_text> ..
  18. UCLA Alzheimer's Disease Research Center
    David B Teplow; Fiscal Year: 2013
    ..Innovations in advancing research are proposed in each Core of this proposal. Each core has responded to criticisms and recommendations from the 2008 review in this renewal application. ..
  19. Studies of Hirano Bodies in Living Cells
    Marcus Fechheimer; Fiscal Year: 2013
    ....
  20. ALZHEIMERS DISEASE RESEARCH CENTER
    John Morris; Fiscal Year: 2013
    ..Changing tau protein levels and tau protein isoforms in mouse models of dementia;(Timothy Miller) 3. APOE metabolism in AD and controls;(Randall Bateman). ..