The
pyruvate-derived
acetyl-CoA is a principal direct precursor substrate for bulk energy synthesis in the brain. Deficits of
pyruvate dehydrogenase in the neocortex are common features of
Alzheimer's disease and other age-related
encephalopathies in humans. Therefore,
amyloid-β overload in brains of diverse transgenic
Alzheimer's disease model animals was investigated as one of neurotoxic compounds responsible for
pyruvate dehydrogenase inhibition yielding deficits of
cholinergic neurotransmission and cognitive functions. Brains of aged, 14-16-month-old Tg2576 mice contained 0.6 μmol/kg levels of amyloid-β1 - 42. Activities of
pyruvate dehydrogenase complex,
choline acetyltransferase, and several
enzymes of
acetyl-CoA and energy metabolism were found to be unchanged in both forebrain mitochondria and synaptosomes of Tg2576 mice, indicating preservation of structural integrity at least in
cholinergic neuronal cells. However, in transgenic brain synaptosomes,
pyruvate utilization, mitochondrial levels, and cytoplasmic
acetyl-CoA levels, as well as
acetylcholine content and its quantal release, were all found to be decreased by 25-40% . On the contrary, activation of
pyruvate utilization was detected and no alterations in
acetyl-CoA content and
citrate or α-ketoglutarate accumulation were observed in transgenic whole brain mitochondria. These data indicate that
amyloid-β evoked deficits in
acetyl-CoA are confined to mitochondrial and cytoplasmic compartments of Tg2576 nerve terminals, becoming early primary signals paving the path for further stages of neurodegeneration. On the other hand,
acetyl-CoA synthesis in mitochondrial compartments of glial cells seems to be activated despite
amyloid-β accumulated in transgenic brains.