APP knockout mice experience acute mortality as the result of ischemia.
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.
Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, California, United States of America.
Maya A
MA
Koike
Alexander J
AJ
Lin
Jonathan
J
Pham
Elaine
E
Nguyen
James J
JJ
Yeh
Rombod
R
Rahimian
Bruce J
BJ
Tromberg
Bernard
B
Choi
Kim N
KN
Green
Frank M
FM
LaFerla
D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000172:deficiency* / Q000235:genetics*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000172:deficiency / Q000235:genetics; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000235:genetics* / Q000401:mortality* / Q000473:pathology / Q000503:physiopathology; D002155:Calsequestrin / Q000378:metabolism; D015687:Cell Hypoxia; D002560:Cerebrovascular Circulation / Q000235:genetics; D055786:Gene Knockout Techniques; D006935:Hypercapnia / Q000503:physiopathology; D051379:Mice; D018384:Oxidative Stress / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism; D059748:Proteolysis; D026362:Serum Response Factor / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D002155:Calsequestrin; D010446:Peptide Fragments; D026362:Serum Response Factor; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse