title: Epidermal growth factor prevents APOE4 and amyloid-beta-induced cognitive and cerebrovascular deficits in female mice.
abstract: Cerebrovascular (CV) dysfunction is emerging as a critical component of Alzheimer's disease (AD), including altered CV coverage. Angiogenic growth factors (AGFs) are key for controlling CV coverage, especially during disease pathology. Therefore, evaluating the effects of AGFs in vivo can provide important information on the role of CV coverage in AD. We recently demonstrated that epidermal growth factor (EGF) prevents amyloid-beta (Aβ)-induced damage to brain endothelial cells in vitro. Here, our goal was to assess the protective effects of EGF on cognition, CV coverage and Aβ levels using an AD-Tg model that incorporates CV relevant AD risk factors. APOE4 is the greatest genetic risk factor for sporadic AD especially in women and is associated with CV dysfunction. EFAD mice express human APOE3 (E3FAD) or APOE4 (E4FAD), overproduce human Aβ42 and are a well characterized model of APOE pathology. Thus, initially the role of APOE and sex in cognitive and CV dysfunction was assessed in EFAD mice in order to identify a group for EGF treatment. At 8 months E4FAD female mice were cognitively impaired, had low CV coverage, high microbleeds and low plasma EGF levels. Therefore, E4FAD female mice were selected for an EGF prevention paradigm (300 μg/kg/wk, 6 to 8.5 months). EGF prevented cognitive decline and was associated with lower microbleeds and higher CV coverage, but not changes in Aβ levels. Collectively, these data suggest that EGF can prevent Aβ-induced damage to the CV. Developing therapeutic strategies based on AGFs may be particularly efficacious for APOE4-induced AD risk.
authors: Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, 60612, USA.
authors: Riya
authors: R
authors: Thomas
authors: Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, 60612, USA.
authors: Paulina
authors: P
authors: Zuchowska
authors: Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, 60612, USA.
authors: Alan W J
authors: AW
authors: Morris
authors: Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, 60612, USA.
authors: Felecia M
authors: FM
authors: Marottoli
authors: Research Histology and Tissue Imaging Core (RHTIC), University of Illinois at Chicago, Chicago, IL, 60612, USA.
authors: Sangeeta
authors: S
authors: Sunny
authors: Research Histology and Tissue Imaging Core (RHTIC), University of Illinois at Chicago, Chicago, IL, 60612, USA.
authors: Ryan
authors: R
authors: Deaton
authors: Research Histology and Tissue Imaging Core (RHTIC), University of Illinois at Chicago, Chicago, IL, 60612, USA.|Department of Pathology, University of Illinois at Chicago, Chicago, IL, 60612, USA.
authors: Peter H
authors: PH
authors: Gann
authors: Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, 60612, USA. leontai@uic.edu.
authors: Leon M
authors: LM
authors: Tai
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D002561:Cerebrovascular Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D060825:Cognitive Dysfunction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018697:Nootropic Agents / Q000494:pharmacology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D012727:Sex Characteristics
chemical_list: D016229:Amyloid beta-Peptides; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D004815:Epidermal Growth Factor
keywords: Alzheimer’s disease; Apolipoprotein E4; Cerebrovasculature; Epidermal growth factor