Altered metabolism of the amyloid beta precursor protein is associated with mitochondrial dysfunction in Down's syndrome.
Most Down's syndrome (DS) patients develop Alzheimer's disease (AD) neuropathology. Astrocyte and neuronal cultures derived from fetal DS brain show alterations in the processing of amyloid beta precursor protein (AbetaPP), including increased levels of AbetaPP and C99, reduced levels of secreted AbetaPP (AbetaPPs) and C83, and intracellular accumulation of insoluble Abeta42. This pattern of AbetaPP processing is recapitulated in normal astrocytes by inhibition of mitochondrial metabolism, consistent with impaired mitochondrial function in DS astrocytes. Intracellular Abeta42 and reduced AbetaPPs are also detected in DS and AD brains. The survival of DS neurons is markedly increased by recombinant or astrocyte-produced AbetaPPs, suggesting that AbetaPPs may be a neuronal survival factor. Thus, mitochondrial dysfunction in DS may lead to intracellular deposition of Abeta42, reduced levels of AbetaPPs, and a chronic state of increased neuronal vulnerability.
Busciglio
Jorge
J
Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA. busciglio@nso1.uchc.edu
Pelsman
Alejandra
A
Wong
Caine
C
Pigino
Gustavo
G
Yuan
Menglan
M
Mori
Hiroshi
H
Yankner
Bruce A
BA
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000209:etiology / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism* / Q000494:pharmacology; D017209:Apoptosis; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D001562:Benzimidazoles / Q000378:metabolism; D002232:Carbocyanines / Q000378:metabolism; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004314:Down Syndrome / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D005333:Fetus / Q000166:cytology; D005456:Fluorescent Dyes / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007223:Infant; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D014475:Uncoupling Agents / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001562:Benzimidazoles; D002232:Carbocyanines; D005456:Fluorescent Dyes; D010446:Peptide Fragments; D011994:Recombinant Proteins; D014475:Uncoupling Agents; C075222:amyloid beta-protein (1-42); C068624:5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone