TY - JOUR
T1 - Targeting vascular amyloid in arterioles of alzheimer disease transgenic mice with amyloid β protein antibody-coated nanoparticles
AU - Poduslo, Joseph F.
AU - Hultman, Kristi L.
AU - Curran, Geoffry L.
AU - Preboske, Gregory M.
AU - Chamberlain, Ryan
AU - Marjanska, Malgorzata
AU - Garwood, Michael
AU - Jack, Clifford R.
AU - Wengenack, Thomas M.
PY - 2011/8
Y1 - 2011/8
N2 - The relevance of cerebral amyloid angiopathy (CAA) to the pathogenesis of Alzheimer disease (AD) and dementia in general emphasizes the importance of developing novel targeting approaches for detecting and treating cerebrovascular amyloid (CVA) deposits. We developed a nanoparticle-based technology that uses a monoclonal antibody against fibrillar human amyloid-β42 that is surface coated onto a functionalized phospholipid monolayer. We demonstrate that this conjugated nanoparticle binds to CVA deposits in arterioles of AD transgenic mice (Tg2576) after infusion into the external carotid artery using 3 different approaches. The first 2 approaches use a blood vessel enrichment of homogenized brain and a leptomeningeal vessel preparation from thin tangential brain slices from the surface of the cerebral cortex. Targeting of CVA by the antibody-coated nanoparticle was visualized using fluorescent lissamine rhodamine-labeled phospholipids in the nanoparticles, which were compared with fluorescent staining of the endothelial cells and amyloiddeposits using confocal laser scanning microscopy. The third approach used high-field strength magnetic resonance imaging of antibody-coated iron oxide nanoparticles after infusion into the externalcarotid artery. Dark foci of contrast enhancement in cortical arterioles were observed in T2*-weighted images of ex vivo AD mouse brains that correlated histologically with CVA deposits. The targeting ability of these nanoparticles to CVA provides opportunities for the prevention and treatment of CAA.
AB - The relevance of cerebral amyloid angiopathy (CAA) to the pathogenesis of Alzheimer disease (AD) and dementia in general emphasizes the importance of developing novel targeting approaches for detecting and treating cerebrovascular amyloid (CVA) deposits. We developed a nanoparticle-based technology that uses a monoclonal antibody against fibrillar human amyloid-β42 that is surface coated onto a functionalized phospholipid monolayer. We demonstrate that this conjugated nanoparticle binds to CVA deposits in arterioles of AD transgenic mice (Tg2576) after infusion into the external carotid artery using 3 different approaches. The first 2 approaches use a blood vessel enrichment of homogenized brain and a leptomeningeal vessel preparation from thin tangential brain slices from the surface of the cerebral cortex. Targeting of CVA by the antibody-coated nanoparticle was visualized using fluorescent lissamine rhodamine-labeled phospholipids in the nanoparticles, which were compared with fluorescent staining of the endothelial cells and amyloiddeposits using confocal laser scanning microscopy. The third approach used high-field strength magnetic resonance imaging of antibody-coated iron oxide nanoparticles after infusion into the externalcarotid artery. Dark foci of contrast enhancement in cortical arterioles were observed in T2*-weighted images of ex vivo AD mouse brains that correlated histologically with CVA deposits. The targeting ability of these nanoparticles to CVA provides opportunities for the prevention and treatment of CAA.
KW - Alzheimer disease
KW - Cerebral amyloid angiopathy
KW - Cerebrovascular amyloid
KW - Confocal laser scanning microscopy
KW - Immunotargeted nanoparticles
KW - Magnetic resonance imaging
UR - http://www.scopus.com/inward/record.url?scp=79961022470&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79961022470&partnerID=8YFLogxK
U2 - 10.1097/NEN.0b013e318225038c
DO - 10.1097/NEN.0b013e318225038c
M3 - Article
C2 - 21760540
AN - SCOPUS:79961022470
SN - 0022-3069
VL - 70
SP - 653
EP - 661
JO - Journal of neuropathology and experimental neurology
JF - Journal of neuropathology and experimental neurology
IS - 8
ER -