Beta-amyloid fragment 25-35 causes mitochondrial dysfunction in primary cortical neurons.
Beta-amyloid deposition and compromised energy metabolism both occur in vulnerable brain regions in Alzheimer's disease. It is not known whether beta-amyloid is the cause of impairment of energy metabolism, nor whether impaired energy metabolism is specific to neurons. Our results, using primary neuronal cultures, show that 24-h incubation with A beta(25-35) caused a generalized decrease in the specific activity of mitochondrial enzymes per milligram of cellular protein, induced mitochondrial swelling, and decreased total mitochondrial number. Incubation with A beta(25-35) decreased ATP concentration to 58% of control in neurons and 71% of control in astrocytes. Levels of reduced glutathione were also lowered by A beta(25-35) in both neurons (from 5.1 to 2.9 nmol/mg protein) and astrocytes (from 25.2 to 14.9 nmol/mg protein). We conclude that 24-h treatment with extracellular A beta(25-35) causes mitochondrial dysfunction in both astrocytes and neurons, the latter being more seriously affected. In astrocytes mitochondrial impairment was confined to complex I inhibition, whereas in neurons a generalized loss of mitochondria was seen.
Casley
C S
CS
Division of Neurochemistry, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, United Kingdom.
Land
J M
JM
Sharpe
M A
MA
Clark
J B
JB
Duchen
M R
MR
Canevari
L
L
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D004622:Embryo, Mammalian; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008933:Mitochondrial Swelling / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C113041:amyloid beta-protein (35-25)