APP knockout mice experience acute mortality as the result of ischemia

• Published in: PloS one Vol. 7; no. 8; p. e42665
• Main Authors: Koike, Maya A, Lin, Alexander J, Pham, Jonathan, Nguyen, Elaine, Yeh, James J, Rahimian, Rombod, Tromberg, Bruce J, Choi, Bernard, Green, Kim N, LaFerla, Frank M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09-08-2012; Public Library of Science (PLoS)
• Subjects: Alzheimer's disease; Amyloid beta-Protein Precursor - deficiency; Amyloid beta-Protein Precursor - genetics; Amyloid Precursor Protein Secretases - deficiency; Amyloid Precursor Protein Secretases - genetics; Animals; Aspartic Acid Endopeptidases - deficiency; Aspartic Acid Endopeptidases - genetics; Biology; Biomedical engineering; Blood; Blood flow; Brain - blood supply; Brain - metabolism; Brain - pathology; Brain - physiopathology; Brain Ischemia - genetics; Brain Ischemia - mortality; Brain Ischemia - pathology; Brain Ischemia - physiopathology; Calcium; Calcium binding proteins; Calsequestrin; Calsequestrin - metabolism; Carotid arteries; Cell adhesion & migration; Cell Hypoxia; Cerebral blood flow; Cerebrovascular Circulation - genetics; Engineering; Gene Knockout Techniques; Health aspects; Hypercapnia - physiopathology; Hypoxia; Ischemia; Lasers; Localization; Medicine; Memory; Mice; Mortality; Mortality risk; Neurological disorders; Oxidative Stress - genetics; Peptide Fragments - metabolism; Proteolysis; Rodents; Serum response factor; Serum Response Factor - metabolism; Traumatic brain injury; Veins & arteries; β-Site APP-cleaving enzyme 1; β-Site APP-cleaving enzymes; United States > US; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0042665

The incidence of Alzheimer's disease increases in people who have had an ischemic episode. Furthermore, APP expression is increased following ischemic or hypoxic conditions, as is the production of the Aβ peptide. To address the question of why APP and Aβ are increased in hypoxic and ischemic conditions we induced an ischemic episode in APP knockout mice (APP-/-) and BACE1 knockout mice (BACE-/-). We find that both APP-/- and BACE-/- mice have a dramatically increased risk of mortality as a result of cerebral ischemia. Furthermore, APP knockout mice have reduced cerebral blood flow in response to hypoxia, while wild-type mice maintain or increase cerebral blood flow to the same conditions. The transcription factor, serum response factor (SRF), and calcium-binding molecule, calsequestrin, both involved in vascular regulation, are significantly altered in the brains of APP-/- mice compared to wild type controls. These results show that APP regulates cerebral blood flow in response to hypoxia, and that it, and its cleavage fragments, are crucial for rapid adaptation to ischemic conditions.