Non-invasive characterization of beta-amyloid(1-40) vasoactivity by functional magnetic resonance imaging in mice.
Neurovascular regulation, which is critical to the efficient functioning of the brain, is impaired in Alzheimer's disease and in transgenic mice overexpressing Abeta. Although senile plaques and neurofibrillary tangles represent neuropathological hallmarks of Alzheimer's disease, deposition of Abeta in cerebral blood vessels also likely plays a significant role in this debilitating and fatal disease. Further, soluble Abeta, which shows greater correlation with disease progression and severity than deposited plaques or tangles, displays strong vasoactive properties. The aim of this study was to develop a non-invasive model of cerebral vasoactivity that would ultimately be translatable to Alzheimer's disease as a marker for disease-modifying efficacy of novel small molecule and biologics drugs. Relative changes in cerebral blood volume following relevant doses of soluble Abeta(1-40) (0.01 or 0.1 mg/mouse), PBS, or the reverse peptide, Abeta(40-1) (0.01 or 0.1 mg/mouse), were monitored non-invasively by contrast-enhanced functional magnetic resonance imaging in anesthetized C57BL/6 mice. Experiments were performed on a 7T horizontal bore scanner using gradient echo echo-planar imaging. As expected, PBS and Abeta(40-1) did not induce any significant change in vascular response. In contrast, Abeta(1-40) significantly decreased CBV in a quantifiable, dose-related and region-specific manner. These data demonstrate for the first time the feasibility of characterizing pathogenic Abeta(1-40)-induced vascular dysfunction in vivo using a non-invasive approach. Further, this technique can be readily applied to preclinical screening in a longitudinal manner for novel drugs or antibodies targeting disease modification.
Experimental Imaging/Advanced Technology, Global Pharmaceutical Research and Development, Abbott Laboratories, R46R, AP9-1, Abbott Park, IL 60064, USA.
F
F
Luo
T R
TR
Seifert
R
R
Edalji
R W
RW
Loebbert
V P
VP
Hradil
J
J
Harlan
M
M
Schmidt
V
V
Nimmrich
B F
BF
Cox
G B
GB
Fox
D000544:Alzheimer Disease / Q000139:chemically induced* / Q000473:pathology*; D016229:Amyloid beta-Peptides; D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000473:pathology*; D001931:Brain Mapping; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D007091:Image Processing, Computer-Assisted / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D010100:Oxygen / Q000097:blood; D010446:Peptide Fragments
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D010100:Oxygen