Microemboli composed of cholesterol crystals disrupt the blood-brain barrier and reduce cognition.
OBJECTIVE
Microemboli occur frequently in patients with asymptomatic carotid atherosclerosis. In other vascular beds, microemboli are known to initiate an inflammatory response, causing organ dysfunction. In the current study, we investigated whether emboli composed of cholesterol crystals, a component of human atherosclerotic plaque, could also cause inflammation and brain dysfunction demonstrated by cognitive impairment.


METHODS
Cholesterol crystals of 60 to 100 microm were injected via the rat internal carotid artery. T2-weighted magnetic resonance imaging was conducted after 3 days to estimate infarct volume. Brains were examined for matrix metalloproteinase activation at 24 hours and for albumin leakage and microglia and astrocyte activation at 4 days and 1, 2, and 4 weeks after embolization. To determine changes in cognition, behavioral tests including open field, motor learning, and Barnes Maze tests were conducted on young adult and middle-aged rats 4 weeks after either a single injection or after repeated, bilateral injections given at an interval of 2 weeks.


RESULTS
Matrix metalloproteinase activation was detected in 50% of the animals examined. Perivascular albumin staining was found at 4 days but rarely persisted beyond 1 week. Activation of microglia and astrocytes occurred in all animals and persisted for up to 8 weeks. Cognitive impairment was observed in middle-aged rats after repeated, bilateral injections but not after single injections. In these animals, areas of inflammation were small and scattered but often involved the striatum and hippocampus.


CONCLUSIONS
Cholesterol embolization caused an inflammatory response in the brain with persistent activation of microglia and astrocytes and led to cognitive impairment after repeated injections in middle-aged animals with only small foci of neural injury. These data indicate that microembolization causes inflammation and that minimal neuronal injury can cause cognitive impairment in older animals.
Department of Surgery, University of California, San Francisco, and the San Francisco Department of Veterans Affairs Medical Center, San Francisco, Calif 94121, USA. rappj@surgery.ucsf.edu
Joseph H
JH
Rapp
Xian Mang
XM
Pan
Melanie
M
Neumann
Michelle
M
Hong
Kelsy
K
Hollenbeck
Jialing
J
Liu
D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D002340:Carotid Artery Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002343:Carotid Artery, Internal; D002784:Cholesterol / Q000737:chemistry / Q000493:pharmacokinetics*; D003072:Cognition Disorders / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D003342:Corpus Striatum / Q000473:pathology; D003460:Crystallization; D004195:Disease Models, Animal; D004660:Encephalitis / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000473:pathology; D020766:Intracranial Embolism / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D002784:Cholesterol