The goal of this Project of our Alzheimer's Disease Research Center is to define the consequences of overexpression or ablation of the amyloid precursor protein (APP) on the phenotype of transgenic animals. A classical feature of cases of Alzheimer's disease (AD) and older individuals with Down's syndrome (DS) is the deposition of the beta- amyloid protein (A-beta) in the cerebral parenchyma and around blood vessels. A-beta is derived from APP and coded for by a gene on human chromosome 21; APP transcripts code for several isoforms, including APP- 695 (enriched in the brain, localized in neurons, and transported rapidly to nerve terminals) and APP-751, a protease inhibitor domain containing isoforms (present in brain and systemic organs). Factors that predispose to amyloidogenesis include: the overexpression of APP; mutations in the APP gene, as documented in some families as early-onset AD; altered APP processing, as occurs in vitro with some APP mutations; and a less well understood contribution by alterations in genes located on chromosomes 14 and 19. Unfortunately, to date, animal models of AD and DS do not reproduce the human phenotype. First, to test the hypothesis that overexpression of APP can lead to A-beta deposits, we have introduced a human APP genomic clone into the mouse germline using yeast artificial chromosome (YAC) cloning vectors and embryonic stem (ES) cells. Animals express transgene products in brain and systemic tissues at levels similar to that of the endogenous APP gene. Animals will be examined over time to determine if they develop amyloid deposits and other AD/DS- related cellular pathology; if so, we will use these animals as models to study the mechanisms of diseases. Second, because APP has been suggested to be a growth factor, a mediator of cell adhesion, a signal transduction protein, a regulator in coagulation cascades, and a participant in neural development, our second aim is to try to define some of the normal functions of APP, particularly in the brain. To investigate the functional roles of APP in mammalian development, the expression of the mouse APP will be ablated gene through gene targeting in ES cells, a strategy that has proved successful for the functional analysis of other genes involved in the development/function of the central nervous system. In concert, these two lines of investigation will provide new information concerning the role of APP overexpression in the development of amyloid deposits and will clarify the roles of APP in mouse development.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG005146-13
Application #
3726323
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Qian, Winnie; Fischer, Corinne E; Schweizer, Tom A et al. (2018) Association Between Psychosis Phenotype and APOE Genotype on the Clinical Profiles of Alzheimer's Disease. Curr Alzheimer Res 15:187-194
Reagh, Zachariah M; Noche, Jessica A; Tustison, Nicholas J et al. (2018) Functional Imbalance of Anterolateral Entorhinal Cortex and Hippocampal Dentate/CA3 Underlies Age-Related Object Pattern Separation Deficits. Neuron 97:1187-1198.e4
Gallagher, Damien; Kiss, Alex; Lanctot, Krista et al. (2018) Depression and Risk of Alzheimer Dementia: A Longitudinal Analysis to Determine Predictors of Increased Risk among Older Adults with Depression. Am J Geriatr Psychiatry 26:819-827
Samus, Quincy M; Black, Betty Smith; Bovenkamp, Diane et al. (2018) Home is where the future is: The BrightFocus Foundation consensus panel on dementia care. Alzheimers Dement 14:104-114
Shi, Liu; Baird, Alison L; Westwood, Sarah et al. (2018) A Decade of Blood Biomarkers for Alzheimer's Disease Research: An Evolving Field, Improving Study Designs, and the Challenge of Replication. J Alzheimers Dis 62:1181-1198
Tse, Kai-Hei; Cheng, Aifang; Ma, Fulin et al. (2018) DNA damage-associated oligodendrocyte degeneration precedes amyloid pathology and contributes to Alzheimer's disease and dementia. Alzheimers Dement 14:664-679
Haaksma, Miriam L; Calderón-Larrañaga, Amaia; Olde Rikkert, Marcel G M et al. (2018) Cognitive and functional progression in Alzheimer disease: A prediction model of latent classes. Int J Geriatr Psychiatry 33:1057-1064
Schaffert, Jeff; LoBue, Christian; White, Charles L et al. (2018) Traumatic brain injury history is associated with an earlier age of dementia onset in autopsy-confirmed Alzheimer's disease. Neuropsychology 32:410-416
Kaji, Seiji; Maki, Takakuni; Kinoshita, Hisanori et al. (2018) Pathological Endogenous ?-Synuclein Accumulation in Oligodendrocyte Precursor Cells Potentially Induces Inclusions in Multiple System Atrophy. Stem Cell Reports 10:356-365
Na, Chan Hyun; Barbhuiya, Mustafa A; Kim, Min-Sik et al. (2018) Discovery of noncanonical translation initiation sites through mass spectrometric analysis of protein N termini. Genome Res 28:25-36

Showing the most recent 10 out of 830 publications