TY - JOUR
T1 - APP knockout mice experience acute mortality as the result of ischemia
AU - Koike, Maya A.
AU - Lin, Alexander J.
AU - Pham, Jonathan
AU - Nguyen, Elaine
AU - Yeh, James J.
AU - Rahimian, Rombod
AU - Tromberg, Bruce J.
AU - Choi, Bernard
AU - Green, Kim N.
AU - LaFerla, Frank M.
PY - 2012/8/9
Y1 - 2012/8/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84865041305&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0042665
DO - 10.1371/journal.pone.0042665
M3 - Article
C2 - 22912719
AN - SCOPUS:84865041305
SN - 1932-6203
VL - 7
JO - PloS one
JF - PloS one
IS - 8
M1 - e42665
ER -