Oligomers of beta-amyloid are sequestered into and seed new plaques in the brains of an AD mouse model.
Amyloid plaque deposition in the brain is a hallmark of Alzheimer's disease, but recent evidence indicates that the disease may be primarily caused by soluble amyloid-beta (1-42) (Abeta) oligomers or Abeta-derived diffusible ligands (ADDLs). ADDLs induce cognitive deficits in animal models and are thought to assemble in vitro by a mechanism apart from plaque formation. To investigate the in vivo relationship of ADDLs and plaques, biotin-labeled ADDLs (bADDLs) or amylin oligomers (bAMs) were injected into the hippocampus of hAPP overexpressing mice. The brains were collected 1 or 5 weeks after the last treatment and were processed for immunohistochemistry. Staining of tissue 1 week post-treatment showed bADDLs had diffused throughout the tissue and incorporated into plaques. Additionally, small deposits of thioflavin S-negative bADDLs were observed. At 5 weeks post-treatment, thioflavin S-positive material continued to accumulate around plaques containing bADDLs. Thioflavin S-positive material also accrued around bADDL deposits, implying that bADDLs were capable of seeding new plaques. In contrast, bAMs cleared from the brain and did not accumulate in plaques. Together, these data indicate that ADDLs are able to contribute to in vivo plaque formation in a peptide-specific manner.
Gaspar
Renee C
RC
Department of Integrative Systems Neuroscience, West Point, PA, USA. renee_gaspar@merck.com
Villarreal
Stephanie A
SA
Bowles
Nicole
N
Hepler
Robert W
RW
Joyce
Joseph G
JG
Shughrue
Paul J
PJ
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D000682:Amyloid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D052160:Benzothiazoles; D001710:Biotin; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D058228:Islet Amyloid Polypeptide; D008024:Ligands; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018625:Microscopy, Atomic Force; D008970:Molecular Weight; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology*; D013844:Thiazoles / Q000378:metabolism
D000682:Amyloid; D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D058228:Islet Amyloid Polypeptide; D008024:Ligands; D010446:Peptide Fragments; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); C009462:thioflavin T; D001710:Biotin