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Patrick Sullivan

Associate Professor Emeritus of Medicine
Medicine, Geriatrics
508 Fulton St., GRECC 182, Durham, NC 27705

Selected Publications


Humanized APOE genotypes influence lifespan independently of tau aggregation in the P301S mouse model of tauopathy.

Journal Article Acta neuropathologica communications · June 2023 Apolipoprotein (APOE) E4 isoform is a major risk factor of Alzheimer's disease and contributes to metabolic and neuropathological abnormalities during brain aging. To provide insights into whether APOE4 genotype is related to tau-associated neurodegenerati ... Full text Cite

Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4.

Journal Article Mol Neurodegener · June 15, 2022 BACKGROUND: Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and the risk of developing late-onset Alzheimer's disease (AD), but the mechanisms for this association are not clear. The activation of calcium-dependent cyto ... Full text Link to item Cite

Impact of APOE genotype on prion-type propagation of tauopathy.

Journal Article Acta Neuropathol Commun · April 19, 2022 Apolipoprotein (APOE) is a major risk factor of Alzheimer's disease (AD), with the E2, E3 and E4 isoforms differentially regulating the burden of AD-associated neuropathologies, such as amyloid β and tau. In AD, pathological tau is thought to spread along ... Full text Link to item Cite

Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4.

Journal Article Mol Neurodegener · April 16, 2021 BACKGROUND: Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and the risk of developing late-onset Alzheimer's disease (AD), but the mechanisms for this association are not clear. The activation of calcium-dependent cyto ... Full text Link to item Cite

APOE4 genetic polymorphism results in impaired recovery in a repeated mild traumatic brain injury model and treatment with Bryostatin-1 improves outcomes.

Journal Article Sci Rep · November 16, 2020 After traumatic brain injury (TBI), some people have worse recovery than others. Single nucleotide polymorphisms (SNPs) in Apolipoprotein E (APOE) are known to increase risk for developing Alzheimer's disease, however there is controversy from human and ro ... Full text Link to item Cite

APOE2 is associated with longevity independent of Alzheimer's disease.

Journal Article Elife · October 19, 2020 Although the ε2 allele of apolipoprotein E (APOE2) benefits longevity, its mechanism is not understood. The protective effects of the APOE2 on Alzheimer's disease (AD) risk, particularly through their effects on amyloid or tau accumulation, may confound AP ... Full text Link to item Cite

25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner.

Journal Article J Neuroinflammation · June 17, 2020 BACKGROUND: Genome-wide association studies of Alzheimer's disease (AD) have implicated pathways related to lipid homeostasis and innate immunity in AD pathophysiology. However, the exact cellular and chemical mediators of neuroinflammation in AD remain po ... Full text Link to item Cite

ApoE mimetic improves pathology and memory in a model of Alzheimer's disease.

Journal Article Brain Res · April 15, 2020 Alzheimer's disease (AD) is the most common form of dementia and is characterized pathologically by Aβ plaques. Current treatments are purely symptomatic despite decades of intensive research interest. Notably, patients with the APOE4 allele are at increas ... Full text Link to item Cite

Intracerebral Expression of AAV-APOE4 Is Not Sufficient to Alter Tau Burden in Two Distinct Models of Tauopathy.

Journal Article Mol Neurobiol · April 2020 Apolipoprotein E4 (APOE4) is the major genetic risk factor for sporadic Alzheimer's disease (AD), which is characterized by amyloid β (Aβ) plaques and tau tangles. Though the role of APOE4 in Aβ pathogenesis has been mechanistically defined in rodent model ... Full text Link to item Cite

APOE genotype regulates pathology and disease progression in synucleinopathy.

Journal Article Sci Transl Med · February 5, 2020 Apolipoprotein E (APOE) ε4 genotype is associated with increased risk of dementia in Parkinson's disease (PD), but the mechanism is not clear, because patients often have a mixture of α-synuclein (αSyn), amyloid-β (Aβ), and tau pathologies. APOE ε4 exacerb ... Full text Link to item Cite

Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model.

Journal Article J Exp Med · November 4, 2019 Chronic activation of brain innate immunity is a prominent feature of Alzheimer's disease (AD) and primary tauopathies. However, to what degree innate immunity contributes to neurodegeneration as compared with pathological protein-induced neurotoxicity, an ... Full text Open Access Link to item Cite

APOE4-mediated amyloid-β pathology depends on its neuronal receptor LRP1.

Journal Article J Clin Invest · March 1, 2019 Carrying the ε4 allele of the APOE gene encoding apolipoprotein E (APOE4) markedly increases the risk for late-onset Alzheimer's disease (AD), in which APOE4 exacerbates the brain accumulation and subsequent deposition of amyloid-β (Aβ) peptides. While the ... Full text Open Access Link to item Cite

Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation.

Journal Article J Clin Invest · May 1, 2018 The apolipoprotein E E4 allele of the APOE gene is the strongest genetic factor for late-onset Alzheimer disease (LOAD). There is compelling evidence that apoE influences Alzheimer disease (AD) in large part by affecting amyloid β (Aβ) aggregation and clea ... Full text Link to item Cite

Age-Dependent Effects of apoE Reduction Using Antisense Oligonucleotides in a Model of β-amyloidosis.

Journal Article Neuron · December 6, 2017 The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer disease. Previous studies suggest that reduction of apoE levels through genetic manipulation can reduce Aβ pathology. However, it is not clear how reduction of a ... Full text Link to item Cite

The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells.

Journal Article Nat Commun · October 11, 2017 Obesity and elevated circulating cholesterol are risk factors for breast cancer recurrence, while the use of statins, cholesterol biosynthesis inhibitors widely used for treating hypercholesterolemia, is associated with improved disease-free survival. Here ... Full text Link to item Cite

ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy.

Journal Article Nature · September 28, 2017 APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer ... Full text Open Access Link to item Cite

Humanized APOE genotypes influence lifespan independently of tau aggregation in the P301S mouse model of tauopathy.

Journal Article Acta neuropathologica communications · June 2023 Apolipoprotein (APOE) E4 isoform is a major risk factor of Alzheimer's disease and contributes to metabolic and neuropathological abnormalities during brain aging. To provide insights into whether APOE4 genotype is related to tau-associated neurodegenerati ... Full text Cite

Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4.

Journal Article Mol Neurodegener · June 15, 2022 BACKGROUND: Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and the risk of developing late-onset Alzheimer's disease (AD), but the mechanisms for this association are not clear. The activation of calcium-dependent cyto ... Full text Link to item Cite

Impact of APOE genotype on prion-type propagation of tauopathy.

Journal Article Acta Neuropathol Commun · April 19, 2022 Apolipoprotein (APOE) is a major risk factor of Alzheimer's disease (AD), with the E2, E3 and E4 isoforms differentially regulating the burden of AD-associated neuropathologies, such as amyloid β and tau. In AD, pathological tau is thought to spread along ... Full text Link to item Cite

Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4.

Journal Article Mol Neurodegener · April 16, 2021 BACKGROUND: Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and the risk of developing late-onset Alzheimer's disease (AD), but the mechanisms for this association are not clear. The activation of calcium-dependent cyto ... Full text Link to item Cite

APOE4 genetic polymorphism results in impaired recovery in a repeated mild traumatic brain injury model and treatment with Bryostatin-1 improves outcomes.

Journal Article Sci Rep · November 16, 2020 After traumatic brain injury (TBI), some people have worse recovery than others. Single nucleotide polymorphisms (SNPs) in Apolipoprotein E (APOE) are known to increase risk for developing Alzheimer's disease, however there is controversy from human and ro ... Full text Link to item Cite

APOE2 is associated with longevity independent of Alzheimer's disease.

Journal Article Elife · October 19, 2020 Although the ε2 allele of apolipoprotein E (APOE2) benefits longevity, its mechanism is not understood. The protective effects of the APOE2 on Alzheimer's disease (AD) risk, particularly through their effects on amyloid or tau accumulation, may confound AP ... Full text Link to item Cite

25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner.

Journal Article J Neuroinflammation · June 17, 2020 BACKGROUND: Genome-wide association studies of Alzheimer's disease (AD) have implicated pathways related to lipid homeostasis and innate immunity in AD pathophysiology. However, the exact cellular and chemical mediators of neuroinflammation in AD remain po ... Full text Link to item Cite

ApoE mimetic improves pathology and memory in a model of Alzheimer's disease.

Journal Article Brain Res · April 15, 2020 Alzheimer's disease (AD) is the most common form of dementia and is characterized pathologically by Aβ plaques. Current treatments are purely symptomatic despite decades of intensive research interest. Notably, patients with the APOE4 allele are at increas ... Full text Link to item Cite

Intracerebral Expression of AAV-APOE4 Is Not Sufficient to Alter Tau Burden in Two Distinct Models of Tauopathy.

Journal Article Mol Neurobiol · April 2020 Apolipoprotein E4 (APOE4) is the major genetic risk factor for sporadic Alzheimer's disease (AD), which is characterized by amyloid β (Aβ) plaques and tau tangles. Though the role of APOE4 in Aβ pathogenesis has been mechanistically defined in rodent model ... Full text Link to item Cite

APOE genotype regulates pathology and disease progression in synucleinopathy.

Journal Article Sci Transl Med · February 5, 2020 Apolipoprotein E (APOE) ε4 genotype is associated with increased risk of dementia in Parkinson's disease (PD), but the mechanism is not clear, because patients often have a mixture of α-synuclein (αSyn), amyloid-β (Aβ), and tau pathologies. APOE ε4 exacerb ... Full text Link to item Cite

Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model.

Journal Article J Exp Med · November 4, 2019 Chronic activation of brain innate immunity is a prominent feature of Alzheimer's disease (AD) and primary tauopathies. However, to what degree innate immunity contributes to neurodegeneration as compared with pathological protein-induced neurotoxicity, an ... Full text Open Access Link to item Cite

APOE4-mediated amyloid-β pathology depends on its neuronal receptor LRP1.

Journal Article J Clin Invest · March 1, 2019 Carrying the ε4 allele of the APOE gene encoding apolipoprotein E (APOE4) markedly increases the risk for late-onset Alzheimer's disease (AD), in which APOE4 exacerbates the brain accumulation and subsequent deposition of amyloid-β (Aβ) peptides. While the ... Full text Open Access Link to item Cite

Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation.

Journal Article J Clin Invest · May 1, 2018 The apolipoprotein E E4 allele of the APOE gene is the strongest genetic factor for late-onset Alzheimer disease (LOAD). There is compelling evidence that apoE influences Alzheimer disease (AD) in large part by affecting amyloid β (Aβ) aggregation and clea ... Full text Link to item Cite

Age-Dependent Effects of apoE Reduction Using Antisense Oligonucleotides in a Model of β-amyloidosis.

Journal Article Neuron · December 6, 2017 The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer disease. Previous studies suggest that reduction of apoE levels through genetic manipulation can reduce Aβ pathology. However, it is not clear how reduction of a ... Full text Link to item Cite

The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells.

Journal Article Nat Commun · October 11, 2017 Obesity and elevated circulating cholesterol are risk factors for breast cancer recurrence, while the use of statins, cholesterol biosynthesis inhibitors widely used for treating hypercholesterolemia, is associated with improved disease-free survival. Here ... Full text Link to item Cite

ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy.

Journal Article Nature · September 28, 2017 APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer ... Full text Open Access Link to item Cite

Apolipoprotein E4 Impairs Neuronal Insulin Signaling by Trapping Insulin Receptor in the Endosomes.

Journal Article Neuron · September 27, 2017 Diabetes and impaired brain insulin signaling are linked to the pathogenesis of Alzheimer's disease (AD). The association between diabetes and AD-associated amyloid pathology is stronger among carriers of the apolipoprotein E (APOE) ε4 gene allele, the str ... Full text Link to item Cite

Complement Factor H Inhibits CD47-Mediated Resolution of Inflammation.

Journal Article Immunity · February 21, 2017 Variants of the CFH gene, encoding complement factor H (CFH), show strong association with age-related macular degeneration (AMD), a major cause of blindness. Here, we used murine models of AMD to examine the contribution of CFH to disease etiology. Cfh de ... Full text Link to item Cite

APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice.

Journal Article Mol Neurodegener · January 31, 2017 BACKGROUND: APOE genotype is the foremost genetic factor modulating β-amyloid (Aβ) deposition and risk of sporadic Alzheimer's disease (AD). Here we investigated how APOE genotype influences response to anti-Aβ immunotherapy. METHODS: APPSW/PS1dE9 (APP) tr ... Full text Link to item Cite

Apolipoprotein E isotype-dependent modulation of microRNA-146a in plasma and brain.

Journal Article Neuroreport · August 3, 2016 The Apolipoprotein E (ApoE) isotype ApoE4 is a prevalent genetic risk factor for Alzheimer's disease (AD) that can modulate systemic and central inflammation, independent of amyloid accumulation. Although disruption of innate immune toll receptor signaling ... Full text Link to item Cite

Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models.

Journal Article Neurobiol Aging · August 2016 The common apolipoprotein E alleles (ε4, ε3, and ε2) are important genetic risk factors for late-onset Alzheimer's disease, with the ε4 allele increasing risk and reducing the age of onset and the ε2 allele decreasing risk and markedly delaying the age of ... Full text Link to item Cite

A Novel Analytic Technique to Measure Associations Between Circulating Biomarkers and Physical Performance Across the Adult Life Span.

Journal Article J Gerontol A Biol Sci Med Sci · February 2016 Understanding associations between circulating biomarkers and physical performance across the adult life span could aid in better describing mechanistic pathways leading to disability. We hypothesized that high concentrations of circulating biomarkers woul ... Full text Link to item Cite

The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer's disease of humans and mice.

Journal Article Neurobiol Aging · January 2016 The apolipoprotein APOE4 allele confers greater risk of Alzheimer's disease (AD) for women than men, in conjunction with greater clinical deficits per unit of AD neuropathology (plaques, tangles). Cerebral microbleeds, which contribute to cognitive dysfunc ... Full text Link to item Cite

Murine versus human apolipoprotein E4: differential facilitation of and co-localization in cerebral amyloid angiopathy and amyloid plaques in APP transgenic mouse models.

Journal Article Acta Neuropathol Commun · November 10, 2015 INTRODUCTION: Amyloid β (Aβ) accumulates in the extracellular space as diffuse and neuritic plaques in Alzheimer's disease (AD). Aβ also deposits on the walls of arterioles as cerebral amyloid angiopathy (CAA) in most cases of AD and sometimes independentl ... Full text Link to item Cite

APOE Isoforms Control Pathogenic Subretinal Inflammation in Age-Related Macular Degeneration.

Journal Article J Neurosci · October 7, 2015 UNLABELLED: Contrary to Alzheimer's disease (AD), the APOE2 allele increases and the APOE4 allele reduces the risk to develop age-related macular degeneration (AMD) compared with the most common APOE3 allele. The underlying mechanism for this association w ... Full text Link to item Cite

Altered neurotransmission in the lateral amygdala in aged human apoE4 targeted replacement mice.

Journal Article Neurobiol Aging · September 2014 The human APOE4 allele is associated with an early age of onset and increased risk of Alzheimer's disease (AD). Apolipoprotein E is secreted as part of a high-density lipoprotein-like particle by glial cells in the brain for the primary purpose of transpor ... Full text Link to item Cite

Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice.

Journal Article Acta Neuropathol Commun · June 28, 2014 Accumulation of β-amyloid (Aβ) in the brain is essential to Alzheimer's disease (AD) pathogenesis. Carriers of the apolipoprotein E (APOE) ε4 allele demonstrate greatly increased AD risk and enhanced brain Aβ deposition. In contrast, APOE ε2 allele carries ... Full text Link to item Cite

Apolipoprotein E-low density lipoprotein receptor interaction affects spatial memory retention and brain ApoE levels in an isoform-dependent manner.

Journal Article Neurobiol Dis · April 2014 Human apolipoprotein E (apoE) exists in three isoforms: apoE2, apoE3 and apoE4. APOE ε4 is a major genetic risk factor for cardiovascular disease (CVD) and Alzheimer's disease (AD). ApoE mediates cholesterol metabolism by binding various receptors. The low ... Full text Link to item Cite

27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology.

Journal Article Science · November 29, 2013 Hypercholesterolemia is a risk factor for estrogen receptor (ER)-positive breast cancers and is associated with a decreased response of tumors to endocrine therapies. Here, we show that 27-hydroxycholesterol (27HC), a primary metabolite of cholesterol and ... Full text Link to item Cite

Western-type diet modulates inflammatory responses and impairs functional outcome following permanent middle cerebral artery occlusion in aged mice expressing the human apolipoprotein E4 allele.

Journal Article J Neuroinflammation · August 20, 2013 BACKGROUND: Numerous clinical trials in stroke have failed, most probably partially due to preclinical studies using young, healthy male rodents with little relevance to the heterogenic conditions of human stroke. Co-morbid conditions such as atheroscleros ... Full text Link to item Cite

Human apolipoprotein E4 worsens acute axonal pathology but not amyloid-β immunoreactivity after traumatic brain injury in 3xTG-AD mice.

Journal Article J Neuropathol Exp Neurol · May 2013 Apolipoprotein E4 (APOE4) genotype is a risk factor for poor outcome after traumatic brain injury (TBI), particularly in young patients, but the underlying mechanisms are not known. By analogy to effects of APOE4 on the risk of Alzheimer disease (AD), the ... Full text Link to item Cite

Blocking the interaction between apolipoprotein E and Aβ reduces intraneuronal accumulation of Aβ and inhibits synaptic degeneration.

Journal Article Am J Pathol · May 2013 Accumulation of β-amyloid (Aβ) in the brain is a key event in Alzheimer disease pathogenesis. Apolipoprotein (Apo) E is a lipid carrier protein secreted by astrocytes, which shows inherent affinity for Aβ and has been implicated in the receptor-mediated Aβ ... Full text Link to item Cite

Estrogen metabolism within the lung and its modulation by tobacco smoke.

Journal Article Carcinogenesis · April 2013 Although estrogen and the enzymes responsible for its metabolism have been detected within the lung, the ability of this tissue to metabolize estrogen has not been demonstrated previously. The goal of this study was to characterize the profile of estrogen ... Full text Link to item Cite

Emergence of a seizure phenotype in aged apolipoprotein epsilon 4 targeted replacement mice.

Journal Article Brain Res · July 27, 2012 The apolipoprotein ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and is associated with earlier age of onset. The incidence of spontaneous seizures has been reported to be increased in sporadic AD as well as in the ... Full text Link to item Cite

Interaction between sex and apolipoprotein e genetic background in a murine model of intracerebral hemorrhage.

Journal Article Transl Stroke Res · March 2012 Emerging evidence suggests sex and apolipoprotein E (APOE) genotype separately modify outcomes after intracerebral hemorrhage (ICH). We test the hypothesis that an interaction exists between sex and APOE polymorphism in modifying outcomes after ICH and is ... Full text Link to item Cite

Disruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human APOE ε4 allele.

Journal Article PLoS One · 2012 Failure of elimination of amyloid-β (Aβ) from the brain and vasculature appears to be a key factor in the etiology of sporadic Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). In addition to age, possession of an apolipoprotein E (APOE) ε4 a ... Full text Link to item Cite

Apolipoprotein E level and cholesterol are associated with reduced synaptic amyloid beta in Alzheimer's disease and apoE TR mouse cortex.

Journal Article Acta Neuropathol · January 2012 The apolipoprotein E4 allele (APOE4) contributes to Alzheimer's disease (AD) risk and APOE2 is protective, but the relevant cellular mechanisms are unknown. We have used flow cytometry analysis to measure apolipoprotein E (apoE) and amyloid beta peptide (A ... Full text Link to item Cite

Anti-amyloid therapy protects against retinal pigmented epithelium damage and vision loss in a model of age-related macular degeneration.

Journal Article Proc Natl Acad Sci U S A · July 12, 2011 Age-related macular degeneration (AMD) is a leading cause of visual dysfunction worldwide. Amyloid β (Aβ) peptides, Aβ1-40 (Aβ40) and Aβ1-42 (Aβ42), have been implicated previously in the AMD disease process. Consistent with a pathogenic role for Aβ, we sh ... Full text Link to item Cite

Reduced levels of human apoE4 protein in an animal model of cognitive impairment.

Journal Article Neurobiol Aging · May 2011 The APOE4 allele is the most common genetic determinant for Alzheimer's disease (AD) in the developed world. APOE genotype specific differences in brain apolipoprotein E protein levels have been observed in numerous studies since the discovery of APOE4's l ... Full text Link to item Cite

APOE-based models of "pre-dementia"

Journal Article Neuromethods · January 11, 2011 Producing a valid animal model of apolipoprotein E (APOE )-based dementia is critical to understanding the etiology and progression of late-onset Alzheimer's disease (AD). Unfortunately, no such model exists. Herein, I review all past and present attempts ... Full text Cite

Progressive loss of synaptic integrity in human apolipoprotein E4 targeted replacement mice and attenuation by apolipoprotein E2.

Journal Article Neuroscience · December 29, 2010 Inheritance of the APOE4 allele is a well established genetic risk factor linked to the development of late onset Alzheimer's disease. As the major lipid transport protein in the central nervous system, apolipoprotein (apo) E plays an important role in the ... Full text Link to item Cite

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

Journal Article J Neurotrauma · November 2010 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 ... Full text Open Access Link to item Cite

Acyclovir or Aβ42 peptides attenuate HSV-1-induced miRNA-146a levels in human primary brain cells.

Journal Article Neuroreport · October 6, 2010 Human brains harbor herpes simplex virus type-1 (HSV-1) DNA, which normally remains quiescent throughout many decades of life. HSV-1 is associated with viral encephalopathy and with the amyloid beta 42 (Abeta42) peptide-enriched lesions that characterize A ... Full text Link to item Cite

LOSS OF SYNAPTIC INTEGRITY IN AGED APOE4 MICE

Journal Article GERONTOLOGIST · October 1, 2010 Link to item Cite

Human APOE isoform-dependent effects on brain beta-amyloid levels in PDAPP transgenic mice.

Journal Article J Neurosci · May 27, 2009 To investigate the role of human apolipoprotein E (apoE) on Abeta deposition in vivo, we crossed PDAPP mice lacking mouse Apoe to targeted replacement mice expressing human apoE (PDAPP/TRE2, PDAPP/TRE3, or PDAPP/TRE4). We then measured the levels of apoE p ... Full text Link to item Cite

ApoE isoform-dependent changes in hippocampal synaptic function.

Journal Article Mol Neurodegener · May 27, 2009 The lipoprotein receptor system in the hippocampus is intimately involved in the modulation of synaptic transmission and plasticity. The association of specific apoE isoform expression with human neurodegenerative disorders has focused attention on the rol ... Full text Link to item Cite

Pharmacogenomic effects of apolipoprotein e on intracerebral hemorrhage.

Journal Article Stroke · February 2009 BACKGROUND AND PURPOSE: The purpose of the study was to evaluate the effect of APOE genotype and the feasibility of administering an apolipoprotein E-mimetic therapeutic to modify outcomes in a murine model of intracerebral hemorrhage. METHODS: Intracerebr ... Full text Link to item Cite

APOE genotype affects outcome in a murine model of sepsis: implications for a new treatment strategy.

Journal Article Anaesth Intensive Care · January 2009 In this study, we assessed whether apolipoprotein E (APOE) polymorphism affects inflammatory responses and mortality in the caecal ligation and puncture model of peritonitis. In addition, we determined the effects of APOE mimetic peptide administration in ... Full text Link to item Cite

Middle-aged human apoE4 targeted-replacement mice show retention deficits on a wide range of spatial memory tasks.

Journal Article Behav Brain Res · November 21, 2008 Featured Publication Apolipoprotein (apo) E4, one of three human apoE (h-apoE) isoforms, has been identified as a major genetic risk factor for Alzheimer's disease and for cognitive deficits associated with aging. However, the biological mechanisms involving apoE in learning a ... Full text Link to item Cite

Human apolipoprotein E4 targeted replacement mice show increased prevalence of intracerebral hemorrhage associated with vascular amyloid deposition.

Journal Article J Stroke Cerebrovasc Dis · September 2008 Featured Publication Previous studies show that APOE *4 carriers are at increased risk for ischemic stroke and intracerebral hemorrhage (ICH). The APOE *4 gene is also linked to increased incidence of cerebral amyloid angiopathy. It has been suggested that apolipoprotein E4 ex ... Full text Link to item Cite

A simple, efficient tool for assessment of mice after unilateral cortex injury.

Journal Article J Neurosci Methods · March 15, 2008 A refined battery of neurological tests, SNAP (Simple Neuroassessment of Asymmetric Impairment), was developed and validated to efficiently assess neurological deficits induced in a mouse model of traumatic brain injury. Four to 7-month old mice were subje ... Full text Link to item Cite

Targeting age-related macular degeneration with Alzheimer's disease based immunotherapies: anti-amyloid-beta antibody attenuates pathologies in an age-related macular degeneration mouse model.

Journal Article Vision Res · February 2008 Age-related macular degeneration (AMD) is a late-onset, neurodegenerative retinal disease that shares several clinical and pathological features with Alzheimer's disease (AD) including extracellular deposits containing amyloid-beta (Abeta) peptides. Immuno ... Full text Link to item Cite

Mortalin is regulated by APOE in hippocampus of AD patients and by human APOE in TR mice.

Journal Article Neurobiol Aging · December 2007 Featured Publication Mortalin is a chaperone protein associated with cell survival, stress response, intracellular trafficking, control of cell proliferation, mitochondrial biogenesis, and cell fate determination. Human APOE targeted replacement (TR) mice have been used to elu ... Full text Link to item Cite

Abeta42 neurotoxicity in primary co-cultures: effect of apoE isoform and Abeta conformation.

Journal Article Neurobiol Aging · August 2007 Featured Publication Autosomal dominant mutations that increase amyloid-beta(1-42) (Abeta42) cause familial Alzheimer's disease (AD), and the most common genetic risk factor for AD is the presence of the epsilon4 allele of apolipoprotein E (apoE). Previously, we characterized ... Full text Link to item Cite

High-fat/high-cholesterol diet promotes a S1P receptor-mediated antiapoptotic activity for VLDL.

Journal Article J Lipid Res · April 2007 Featured Publication Withdrawing growth factors or serum from endothelial cells leads to the activation of effector caspases 3 and 7, resulting in apoptotic cell death. HDL protects against caspase induction through sphingosine-1-phosphate (S1P) receptors. This anti-caspase ac ... Full text Link to item Cite

Apolipoprotein E modifies the CNS response to injury via a histamine-mediated pathway.

Journal Article Neurol Res · April 2007 Recent evidence demonstrates that apolipoprotein E (apoE) influences the central nervous system (CNS) response to both acute and chronic injury. To address the mechanisms by which apoE influences neurological disease, we examined differential gene expressi ... Full text Link to item Cite

An apolipoprotein E-based therapeutic improves outcome and reduces Alzheimer's disease pathology following closed head injury: evidence of pharmacogenomic interaction.

Journal Article Neuroscience · February 23, 2007 Featured Publication Apolipoprotein E (apoE) modifies glial activation and the CNS inflammatory response in an isoform-specific manner. Peptides derived from the receptor-binding region of apoE have been demonstrated to maintain the functional activity of the intact protein, a ... Full text Link to item Cite

Estradiol enhances long term potentiation in hippocampal slices from aged apoE4-TR mice.

Journal Article Hippocampus · 2007 Featured Publication Hormone replacement therapy to treat or prevent Alzheimer Disease (AD) in postmenopausal women is controversial because it may pose other health risks such as cancer and thromboembolism. ApoE status is thought to influence the nootropic efficacy of hormone ... Full text Link to item Cite

Amyloid-beta1-42 reduces neuronal excitability in mouse dentate gyrus.

Journal Article Neurosci Lett · July 31, 2006 Featured Publication Amyloid-beta (Abeta) is causally implicated in Alzheimer's disease and neuroplasticity failure has acquired validity as a possible mechanism of early AD pathogenesis. We have previously demonstrated that oligomeric Abeta(1-42) inhibits LTP in the dentate g ... Full text Link to item Cite

A deficit in astroglial organization causes the impaired reactive sprouting in human apolipoprotein E4 targeted replacement mice.

Journal Article Neurobiol Dis · March 2006 Featured Publication The epsilon4 allele of apolipoprotein (apo)E associates with an increased risk of developing Alzheimer's disease (AD) as well as an earlier age of onset. However, the exact mechanisms by which apoE4 confers such susceptibility is currently unknown. We used ... Full text Link to item Cite

Blockade of nicotinic acetylcholine receptors suppresses hippocampal long-term potentiation in wild-type but not ApoE4 targeted replacement mice.

Journal Article J Neurosci Res · December 15, 2005 Both impaired nicotinic neurotransmission and the inheritance of apoE4 are associated with increased risk for Alzheimer disease (AD) as well as other deficiencies in memory-related behavior. Long-term potentiation (LTP), a cellular model of memory, is know ... Full text Link to item Cite

Apolipoprotein E allele-dependent pathogenesis: a model for age-related retinal degeneration.

Journal Article Proc Natl Acad Sci U S A · August 16, 2005 Featured Publication Age-related macular degeneration (AMD) is a late-onset, multifactorial, neurodegenerative disease of the retina and the leading cause of irreversible vision loss in the elderly in the Western world. We describe here a murine model that combines three known ... Full text Link to item Cite

The low density lipoprotein receptor regulates the level of central nervous system human and murine apolipoprotein E but does not modify amyloid plaque pathology in PDAPP mice.

Journal Article J Biol Chem · July 8, 2005 Featured Publication Apolipoprotein E (apoE), a chaperone for the amyloid beta (Abeta) peptide, regulates the deposition and structure of Abeta that deposits in the brain in Alzheimer disease (AD). The primary apoE receptor that regulates levels of apoE in the brain is unknown ... Full text Link to item Cite

Human apoE targeted replacement mouse lines: h-apoE4 and h-apoE3 mice differ on spatial memory performance and avoidance behavior.

Journal Article Behav Brain Res · April 15, 2005 Featured Publication Apolipoprotein E4 (apoE4), one of the three most common human apoE (h-apoE) isoforms, is a major genetic risk factor for Alzheimer's disease and for cognitive deficits associated with aging. The biological mechanisms involving apoE in learning and memory p ... Full text Link to item Cite

Human apolipoprotein E4 alters the amyloid-beta 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model.

Journal Article J Neurosci · March 16, 2005 Alzheimer's disease (AD) is characterized by the aggregation and deposition of the normally soluble amyloid-beta (Abeta) peptide in the extracellular spaces of the brain as parenchymal plaques and in the walls of cerebral vessels as cerebral amyloid angiop ... Full text Link to item Cite

Human apoE4-targeted replacement mice display synaptic deficits in the absence of neuropathology.

Journal Article Neurobiol Dis · March 2005 Featured Publication The human APOE*4 allele is associated with an early age of onset and increased risk of Alzheimer's disease (AD). Long before the onset of AD, cognitive deficits can be identified in APOE*4 carriers. We examined neurons in the lateral amygdala of young apol ... Full text Link to item Cite

ApoE isoform-specific effects on LTP: blockade by oligomeric amyloid-beta1-42.

Journal Article Neurobiol Dis · February 2005 Amyloid-beta1-42 (Abeta1-42) is crucial to Alzheimer disease (AD) pathogenesis but the conformation of the toxic Abeta species remains uncertain. AD risk is increased by apolipoprotein E4 (apoE4) and decreased by apoE2 compared with the apoE3 isoform, but ... Full text Link to item Cite

Production and characterization of astrocyte-derived human apolipoprotein E isoforms from immortalized astrocytes and their interactions with amyloid-beta.

Journal Article Neurobiol Dis · 2005 Featured Publication The apolipoprotein E (apoE) genotype is an important genetic risk factor for Alzheimer's disease (AD). In the central nervous system (CNS), most apoE is produced by astrocytes and is present in unique high-density lipoprotein (HDL)-like particles that have ... Full text Link to item Cite

ApoE isoform affects LTP in human targeted replacement mice.

Journal Article Neuroreport · December 3, 2004 Inheritance of the epsilon4 allele for apolipoprotein E (apoE) increases the risk of Alzheimer disease and memory impairment, whereas epsilon2 decreases these risks compared with the most common epsilon3 allele, but the mechanism for these effects is unkno ... Full text Link to item Cite

Marked regional differences of brain human apolipoprotein E expression in targeted replacement mice.

Journal Article Neuroscience · 2004 Featured Publication We used three human apolipoprotein (apo) E targeted replacement mouse lines, each expressing one of the three common human apoE isoforms to study the pattern of apoE expression in the central nervous system (CNS). Immunocytochemistry on brain sections from ... Full text Link to item Cite

APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response.

Journal Article J Biol Chem · December 5, 2003 Human apolipoprotein E is the major apolipoprotein expressed in the brain and exists as three isoforms, designated E2, E3, and E4. Although evidence suggests that apolipoprotein E plays an important role in modifying systemic and brain inflammatory respons ... Full text Link to item Cite

ApoE genotype-specific inhibition of apoptosis.

Journal Article J Lipid Res · August 2003 Endothelial cell apoptosis can be initiated by withdrawing growth factors or serum, and is inhibited by HDL. Our results show that the total lipoprotein population from apolipoprotein E 4/4 (APOE4/4) sera is less anti-apoptotic than total lipoproteins from ... Full text Link to item Cite

Effect of diet and targeted replacement human APOE isoforms in aged mice

Conference INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE · May 1, 2003 Link to item Cite

ApoB-48 and apoB-100 differentially influence the expression of type-III hyperlipoproteinemia in APOE*2 mice.

Journal Article J Lipid Res · September 2002 Apolipoprotein E (apoE) is essential for the clearance of plasma chylomicron and VLDL remnants. The human APOE locus is polymorphic and 5-10% of APOE*2 homozygotes exhibit type-III hyperlipoproteinemia (THL), while the remaining homozygotes have less than ... Full text Link to item Cite

Apolipoprotein E isoform mediated regulation of nitric oxide release.

Journal Article Free Radic Biol Med · June 1, 2002 Progressive dysfunction and death of neurons in Alzheimer's dementia is enhanced in patients carrying one or more APOE4 alleles who also display increased presence of oxidative stress markers. Modulation of oxidative stress is a nontraditional and physiolo ... Full text Link to item Cite

Purification and characterization of astrocyte-secreted apolipoprotein E and J-containing lipoproteins from wild-type and human apoE transgenic mice.

Journal Article Neurochem Int · 2001 Featured Publication The varepsilon4 allele of apolipoprotein E (apoE) is a genetic risk factor for Alzheimer's disease (AD). In order to gain a better understanding of the molecular mechanisms by which apoE and possibly other apolipoproteins produced in the central nervous sy ... Full text Link to item Cite

Apo E structure determines VLDL clearance and atherosclerosis risk in mice.

Journal Article J Clin Invest · June 1999 Featured Publication We have generated mice expressing the human apo E4 isoform in place of the endogenous murine apo E protein and have compared them with mice expressing the human apo E3 isoform. Plasma lipid and apolipoprotein levels in the mice expressing only the apo E4 i ... Full text Link to item Cite

Type III hyperlipoproteinemia and spontaneous atherosclerosis in mice resulting from gene replacement of mouse Apoe with human Apoe*2.

Journal Article J Clin Invest · July 1, 1998 Featured Publication To study isoform-specific effects of apolipoprotein E (apoE) in vivo, we generated mice with a human APOE*2 allele in place of the mouse Apoe gene via targeted gene replacement in embryonic stem cells. Mice expressing human apoE2 (2/2) have virtually all t ... Full text Link to item Cite

Cis-acting human ApoE tissue expression element is associated with human pattern of intraneuronal ApoE in transgenic mice.

Journal Article Neurobiol Aging · 1998 Apolipoprotein E polymorphic variants (ApoE-epsilon2, epsilon3, and epsilon4) are associated with the age of onset distribution and risk of Alzheimer disease. The question of whether ApoE is expressed at a comparatively low level in human neurons compared ... Full text Link to item Cite

Targeted replacement of the mouse apolipoprotein E gene with the common human APOE3 allele enhances diet-induced hypercholesterolemia and atherosclerosis.

Journal Article J Biol Chem · July 18, 1997 Featured Publication Apolipoprotein (apo) E, a constituent of several lipoproteins, is a ligand for the low density lipoprotein receptor, and this interaction is important for maintaining cholesterol and triglyceride homeostasis. We have used a gene replacement strategy to gen ... Full text Link to item Cite

Overexpression of androgen-binding protein/sex hormone-binding globulin in male transgenic mice: tissue distribution and phenotypic disorders.

Journal Article Biol Reprod · January 1997 The rat androgen-binding protein/sex hormone-binding globulin (ABP/SHBG) gene in transgenic mice was previously shown to be specifically expressed in the testes. This study verifies a Sertoli cell location of ABP and translation of testicular ABP mRNA in t ... Full text Link to item Cite

Distribution of immunoreactive androgen-binding protein/sex hormone-binding globulin in tissues of the fetal rat.

Journal Article Steroids · July 1996 Androgen-binding protein/sex hormone-binding globulin (ABP/SHBG) is an extracellular carrier protein that binds androgens and estrogens with high affinity. In the adult, ABP/SHBG is thought to function in the male reproductive system and the general circul ... Full text Link to item Cite

Human apolipoprotein E2, E3, and E4 isoform-specific transgenic mice: human-like pattern of glial and neuronal immunoreactivity in central nervous system not observed in wild-type mice.

Journal Article Neurobiol Dis · 1996 Apolipoprotein E (apoE) and its three major alleles (APOE2, E3, and E4) have been implicated in Alzheimer's disease and other neurological disorders. Little is known of the role apoE plays in normal brain function and pathology. To create a model to study ... Full text Link to item Cite

Tissue-specific expression of the rat androgen-binding protein/sex hormone-binding globulin gene in transgenic mice.

Journal Article Mol Cell Endocrinol · October 1993 The testicular Sertoli cell produces an extracellular androgen-binding protein (ABP) that binds testosterone and dihydrotestosterone with high affinity. The ABP gene also encodes plasma sex hormone-binding globulin (SHBG), which is produced by the liver of ... Full text Link to item Cite

Identification of an alternate promoter in the rat androgen-binding protein/sex hormone-binding globulin gene that regulates synthesis of a messenger RNA encoding a protein with altered function.

Journal Article Mol Endocrinol · May 1993 Extracellular androgen-binding proteins (ABP) are thought to modulate the regulatory functions of androgens. These proteins, which are secreted by the testis (ABP) and liver [sex hormone-binding globulin (SHBG)], are encoded by the same gene. In a previous ... Full text Link to item Cite

Alternative processing of androgen-binding protein RNA transcripts in fetal rat liver. Identification of a transcript formed by trans splicing.

Journal Article J Biol Chem · January 5, 1991 Androgens and their nuclear receptor regulate genes necessary for development of the male phenotype, a process that is thought to be modulated by extracellular androgen carrier proteins. Two of these carrier proteins, testicular androgen-binding protein (A ... Link to item Cite

Complex structure and regulation of the ABP/SHBG gene.

Journal Article J Steroid Biochem Mol Biol · 1991 Extracellular androgen-binding proteins (ABPs) are thought to modulate the regulatory functions of androgens and the trans-acting nuclear androgen receptor. Testicular ABP and plasma sex hormone-binding globulin (SHBG), which is produced in the liver, are ... Full text Link to item Cite

Characterization and expression of the complementary DNA encoding rat histidine decarboxylase.

Journal Article Proc Natl Acad Sci U S A · January 1990 Histamine is a neurotransmitter in the central nervous system and an important modulator of gastric acid secretion, vasomotor control, inflammation, and allergic reactions. In biological systems the formation of histamine from its precursor histidine is ca ... Full text Link to item Cite

Erratum: Characterization and expression of the complementary DNA encoding rat histidine decarboxylase (Proc. Natl. Acad. Sci. USA (1990) 87 (733-737))

Journal Article Proceedings of the National Academy of Sciences of the United States of America · January 1, 1990 Full text Cite

The androgen-binding protein gene is expressed in CD1 mouse testis.

Journal Article Mol Cell Endocrinol · May 1989 Androgen-binding protein (ABP) is a testicular Sertoli cell secretory protein that acts as a carrier of androgen in the male reproductive tract. ABP has been characterized from a wide range of animal species, including man, rabbit and rat. However, it has ... Full text Link to item Cite

Cloning of human androgen receptor complementary DNA and localization to the X chromosome.

Journal Article Science · April 15, 1988 The androgen receptor (AR) mediates the actions of male sex steroids. Human AR genomic DNA was cloned from a flow-sorted human X chromosome library by using a consensus nucleotide sequence from the DNA-binding domain of the family of nuclear receptors. The ... Full text Link to item Cite