Amyloid beta interacts with the amyloid precursor protein: a potential toxic mechanism in Alzheimer's disease.
Amyloid beta protein (Abeta) deposition in the brain is a hallmark of Alzheimer's disease (AD). The fibrillar form of Abeta is neurotoxic, although the mechanism of its toxicity is unknown. We showed that conversion of Abeta to the fibrillar form markedly increased binding to specific neuronal membrane proteins, including amyloid precursor protein (APP). Nanomolar concentrations of fibrillar Abeta bound cell-surface holo-APP in cortical neurons. Reduced vulnerability of cultured APP-null neurons to Abeta neurotoxicity suggested that Abeta neurotoxicity involves APP. Thus Abeta toxicity may be mediated by the interaction of fibrillar Abeta with neuronal membrane proteins, notably APP. An Abeta-APP interaction reminiscent of the pathogenic mechanism of prions may thus contribute to neuronal degeneration in AD.
Lorenzo
A
A
Department of Neurology, Harvard Medical School, The Children's Hospital, Boston, MA 02115, USA.
Yuan
M
M
Zhang
Z
Z
Paganetti
P A
PA
Sturchler-Pierrat
C
C
Staufenbiel
M
M
Mautino
J
J
Vigo
F S
FS
Sommer
B
B
Yankner
B A
BA
D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism* / Q000633:toxicity*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001704:Biopolymers / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000633:toxicity; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology / Q000473:pathology; D017353:Gene Deletion; D006624:Hippocampus / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D051381:Rats; D012995:Solubility
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001704:Biopolymers; D008565:Membrane Proteins