Extracellular amyloid formation and associated pathology in neural grafts.
Amyloid precursor protein (APP) processing and the generation of beta-amyloid peptide (Abeta) are important in the pathogenesis of Alzheimer's disease. Although this has been studied extensively at the molecular and cellular levels, much less is known about the mechanisms of amyloid accumulation in vivo. We transplanted transgenic APP23 and wild-type B6 embryonic neural cells into the neocortex and hippocampus of both B6 and APP23 mice. APP23 grafts into wild-type hosts did not develop amyloid deposits up to 20 months after grafting. In contrast, both transgenic and wild-type grafts into young transgenic hosts developed amyloid plaques as early as 3 months after grafting. Although largely diffuse in nature, some of the amyloid deposits in wild-type grafts were congophilic and were surrounded by neuritic changes and gliosis, similar to the amyloid-associated pathology previously described in APP23 mice. Our results indicate that diffusion of soluble Abeta in the extracellular space is involved in the spread of Abeta pathology, and that extracellular amyloid formation can lead to neurodegeneration.
Meyer-Luehmann
Melanie
M
Department of Neuropathology, Institute of Pathology, University of Basel, Schönbeinstrasse 40, CH-4003 Basel, Switzerland.
Stalder
Martina
M
Herzig
Martin C
MC
Kaeser
Stephan A
SA
Kohler
Esther
E
Pfeifer
Michelle
M
Boncristiano
Sonia
S
Mathews
Paul M
PM
Mercken
Marc
M
Abramowski
Dorothee
D
Staufenbiel
Matthias
M
Jucker
Mathias
M
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016380:Brain Tissue Transplantation; D004058:Diffusion; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000235:genetics / Q000378:metabolism*; D005911:Gliosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006085:Graft Survival / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology / Q000637:transplantation; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport / Q000235:genetics; D011930:Reaction Time / Q000235:genetics; D012995:Solubility; D015854:Up-Regulation / Q000235:genetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor