Intracranially administered anti-Abeta antibodies reduce beta-amyloid deposition by mechanisms both independent of and associated with microglial activation.
Active immunization against the beta-amyloid peptide (Alphabeta) with vaccines or passive immunization with systemic monoclonal anti-Abeta antibodies reduces amyloid deposition and improves cognition in APP transgenic mice. In this report, intracranial administration of anti-Alphabeta antibodies into frontal cortex and hippocampus of Tg2576 transgenic APP mice is described. The antibody injection resulted initially in a broad distribution of staining for the antibody, which diminished over 7 d. Although no loss of immunostaining for deposited Abeta was apparent at 4 hr, a dramatic reduction in the Alphabeta load was discernible at 24 hr and was maintained at 3 and 7 d. A reduction in the thioflavine-S-positive compact plaque load was delayed until 3 d, at which time microglial activation also became apparent. At 1 week after the injection, microglial activation returned to control levels, whereas Alphabeta and thioflavine-S staining remained reduced. The results from this study suggest a two-phase mechanism of anti-Alphabeta antibody action. The first phase occurs between 4 and 24 hr, clears primarily diffuse Alphabeta deposits, and is not associated with observable microglial activation. The second phase occurs between 1 and 3 d, is responsible for clearance of compact amyloid deposits, and is associated with microglial activation. The results are discussed in the context of other studies identifying coincident microglial activation and amyloid removal in APP transgenic animals.
Department of Pharmacology, Alzheimer's Research Laboratory, University of South Florida, Tampa, Florida 33612, USA.
Donna M
DM
Wilcock
Giovanni
G
DiCarlo
Debbi
D
Henderson
Jennifer
J
Jackson
Keisha
K
Clarke
Kenneth E
KE
Ugen
Marcia N
MN
Gordon
Dave
D
Morgan
D000367:Age Factors; D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage*; D052160:Benzothiazoles; D004333:Drug Administration Routes; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D007116:Immunization, Passive / Q000379:methods; D007150:Immunohistochemistry; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053764:Presenilin-1; D013844:Thiazoles / Q000378:metabolism; D013997:Time Factors
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D052160:Benzothiazoles; D000949:Histocompatibility Antigens Class II; D008565:Membrane Proteins; D053764:Presenilin-1; D013844:Thiazoles; C009462:thioflavin T; D017493:Leukocyte Common Antigens