Differential activation of mitochondrial apoptotic pathways by vasculotropic amyloid-beta variants in cells composing the cerebral vessel walls.
Cerebral amyloid angiopathy (CAA) is an age-associated condition and a common finding in Alzheimer's disease in which amyloid-beta (Abeta) vascular deposits are featured in >80% of the cases. Familial Abeta variants bearing substitutions at positions 21-23 are primarily associated with CAA, although they manifest with strikingly different clinical phenotypes: cerebral hemorrhage or dementia. The recently reported Piedmont L34V Abeta mutant, located outside the hot spot 21-23, shows a similar hemorrhagic phenotype, albeit less aggressive than the widely studied Dutch E22Q variant. We monitored the apoptotic events occurring after stimulation of human brain microvascular endothelial and smooth muscle cells with nonfibrillar structures of both variants and wild-type Abeta40. Induction of analogous caspase-mediated mitochondrial pathways was elicited by all peptides, although within different time frames and intensity. Activated pathways were susceptible to pharmacological modulation either through direct inhibition of mitochondrial cytochrome c release or by the action of pan- and pathway-specific caspase inhibitors, giving a clear indication of the independent or synergistic engagement of both extrinsic and intrinsic mechanisms. Structural analyses of the Abeta peptides showed that apoptosis preceded fibril formation, correlating with the presence of oligomers and/or protofibrils. The data support the notion that rare genetic mutations constitute unique paradigms to understand the molecular pathogenesis of CAA.
Fossati
S
S
Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
Cam
J
J
Meyerson
J
J
Mezhericher
E
E
Romero
I A
IA
Couraud
P O
PO
Weksler
B B
BB
Ghiso
J
J
Rostagno
A
A
D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017209:Apoptosis; D001921:Brain / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D028243:Cerebral Amyloid Angiopathy, Familial / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D045304:Cytochromes c / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D014644:Genetic Variation; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D011994:Recombinant Proteins; D045304:Cytochromes c; D020169:Caspases