AβPP-Transgenic 2576 Mice Mimic Cell Type-Specific Aspects of Acetyl-CoA-Linked Metabolic Deficits in Alzheimer’s Disease

Abstract

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.

Early and Late Pathomechanisms in Alzheimer’s Disease: From Zinc to Amyloid-β Neurotoxicity

“…The sources of these discrepancies remain unsolved. Among others, there is not known how these processes could be affected by acetyl-CoA availability in the cytoplasmic compartment, which is likely to be reduced in these pathologies [43]. Such thesis is justified by the fact that concentration of acetyl-CoA in cytoplasmic compartments of nerve terminals or clonal neuronal cell bodies (0.003–0.005 mmol/L), appeared to be several times lower than its Km for AT-1-mediated transport to endoplasmic reticulum (0.014 mmol/L) [30, 36, 44–46].…”

“…Intraterminal mitochondria contained similar or somewhat higher levels of acetyl-CoA as whole brain mitochondria derived for neuronal perikaryons and glial cells [43, 49, 57]. They were apparently sufficient for feeding tricarboxylic acid cycle and maintain nerve terminal viability, including their neurotransmitter functions, under in vitro conditions [57–60].…”

“…The level of synaptoplasmic acetyl-CoA depends on rates of its generation in mitochondria and transport through their inner membrane. The inhibition of pyruvate dehydrogenase in vivo by thiamine deficits, brain amyloidosis or in vitro by aluminum, NO excess or 3-bromopyruvate resulted in decrease of acetyl-CoA transport to synaptoplasm yielding decrease of intraterminal ACh content and release [34, 43, 45, 57]. Inhibitors of acetyl-CoA transport out of the mitochondria attenuated ACh metabolism, without affecting PDHC activity (see preceeding chapter).…”

“…Different TgAD mice models accumulate variable concentrations of Aβ in their brains corresponding to wide range of the peptide levels detected in human AD victims [43, 117, 145]. Thereby, they constitute a good model to study in vivo pathomechanisms of Aβ in AD including energy metabolism and neurotransmitter functions.…”

“…All of them demonstrate age-progressing amyloidosis accompanied by cognitive deficits [145, 148]. The 2576Tg hemizygous mice containing human APP695 gen with K670N/M671L mutations, at age of 15 month developed deep cognitive deficits at Aβ load of 0.4–0.6 μmol/kg brain wet weight [43]. Such level corresponded to that seen in AD human brain, in which significant functional and structural impairment of energy metabolism took place [98, 117, 149, 150].…”