Traumatic brain injury exacerbates neurodegenerative pathology: improvement with an apolipoprotein E-based therapeutic.

Loading...
Thumbnail Image

Date

2010-11

Journal Title

Journal ISSN

Volume Title

Repository Usage Stats

390
views
1035
downloads

Citation Stats

Attention Stats

Abstract

Cognitive impairment is common following traumatic brain injury (TBI), and neuroinflammatory mechanisms may predispose to the development of neurodegenerative disease. Apolipoprotein E (apoE) polymorphisms modify neuroinflammatory responses, and influence both outcome from acute brain injury and the risk of developing neurodegenerative disease. We demonstrate that TBI accelerates neurodegenerative pathology in double-transgenic animals expressing the common human apoE alleles and mutated amyloid precursor protein, and that pathology is exacerbated in the presence of the apoE4 allele. The administration of an apoE-mimetic peptide markedly reduced the development of neurodegenerative pathology in mice homozygous for apoE3 as well as apoE3/E4 heterozygotes. These results demonstrate that TBI accelerates the cardinal neuropathological features of neurodegenerative disease, and establishes the potential for apoE mimetic therapies in reducing pathology associated with neurodegeneration.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1089/neu.2010.1396

Publication Info

Laskowitz, Daniel T, Pingping Song, Haichen Wang, Brian Mace, Patrick M Sullivan, Michael P Vitek and Hana N Dawson (2010). Traumatic brain injury exacerbates neurodegenerative pathology: improvement with an apolipoprotein E-based therapeutic. J Neurotrauma, 27(11). pp. 1983–1995. 10.1089/neu.2010.1396 Retrieved from https://hdl.handle.net/10161/3293.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.

Scholars@Duke

Wang

Haichen Wang

Assistant Professor in Neurology
Sullivan

Patrick Sullivan

Associate Professor Emeritus of Medicine

The primary focus of my lab is to investigate the relationship between APOE genotype and late onset Alzheimer’s disease (AD).  The single most common and influential gene in AD is the APOE gene.  The APOE gene is polymorphic; encoding three different alleles designated APOE2, E3 or E4.  APOE4 carriers have the highest risk for AD while APOE3 carriers have an essentially neutral risk and APOE2 carriers may be protected against AD.  The APOE4 gene is also linked to increased risk for atherosclerosis, cerebral amyloid angiopathy, peripheral neuropathy, multiple sclerosis, stroke and type II diabetes; as well as an increased susceptibility to HIV and Chlamydia infections, head injury and cognitive decline following coronary bypass surgery.  The fact that 28% of the US population are carriers of the APOE4 gene, underscores the need for a better understanding of APOE’s relationship to disease.  The major challenge facing researchers today is determining why some APOE4 carriers succumb to disease while others do not.  Genetic modifiers and environmental risk factors likely explain different individual outcomes. The primary environmental risk factors are thought to be; a Westernized diet, low physical activity, chronic stress, poor sleep habits, andro/menopause and most importantly, age.

We are currently working to test novel drug formulations that specifically target putative apoE dependent mechanisms involved in neurodegeneration.  Our initial screens involve neuronal-glial cell culture models that eventually will lead to testing in animals.  We currently use the best available animal model of apoE-linked AD, the human apoE targeted replacement (TR) or “knock in” mice.  I created three lines of human apoE TR mice, each expressing one the three human apoE isoforms and have since made multiple crosses to other AD related genes (e.g. APP, PS1 and tau).  I have given the apoE TR mice and made the crosses available to over 70 labs worldwide.

We are also working to build a better model of late onset AD by combining the apoE TR mice with non-mutated human APP and tau KI mice.  We think this is important because over 98% of all AD cases contain no mutations in the APP or tau genes.  Our hope is to better understand the true etiology and progression of late onset AD.  If successful this new model should aid in both novel target identification and new drug testing to produce therapeutics with greater efficacy in treating AD.

Dawson

Hana Nenicka Dawson

Adjunct Assistant Professor in the Department of Neurology

Our laboratory studies the role of tau protein in neurodegeneration. Aggregated tau protein is a hallmark feature of a group of neurodegenerative dementias called tauopathies. This group of diseases accounts for a large majority of all dementias and includes Alzheimer's disease, Pick's disease and frontotemporal dementia to name a few.
To model tauopathies, we overexpressed normal and mutated human tau protein or no tau protein in the central nervous system of transgenic mice. Several of these models replicate the human disease and acquired age-dependent central nervous system pathology. Utilizing these diverse models with molecular, cellular and whole animal techniques, our goal is to clarify the role of tau related neuropathology and to uncover strategies with which to treat human tauopathies.
By crossbreeding our models to other transgenic mice we are examining mechanisms of Alzheimer’s disease, frontotemporal dementia, amyotrophic lateral sclerosis and head injury. We also collaborate with clinical colleagues to bridge the gap between basic and clinical research.


Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.