Interactions of early and late neurotoxic signals in cholinergic neurodegeneration
The loss of neurons and suppression of energy metabolism, in pathology‑affected areas of the brain, are characteristic features of several neurodegenerative conditions including Alzheimer’s disease, and vascular, dialysis, alcohol, liver, or thiamine deficiency encephalopathies. Multiple acute neurotoxic insults such as transient hypoxia, hypoglycemia, or xenobiotics generating excess of free radicals, glutamate-Zn excitotoxic stimulation, trace metal dis-homeostasis, inhibition of energy metabolism, may pave the path for subsequent stages of neurodegeneration. This presentation basing on cellular, animal models of neurotoxicity and clinical-laboratory medicine data, describes putative mechanisms linking early pathological alterations in energy‑acetyl‑CoA metabolism with late stages of different cholinergic encephalopathies. Preferential impairment of basal forebrain cholinergic neurons is blamed for appearance of cognitive deficits leading to dementia in final stages of these pathologies. This phenomenon may result from the fact that cholinergic neurons, unlike other ones utilize a direct key energy precursor metabolite – acetyl-CoA, de rived from glucose, not only for ATP and N-acetylaspartate synthesis but also for acetylcholine production. Cholinergic neurons also possess greater than noncholinergic ones and glial cells zinc accumulation capacity. Such properties promote amyloidogenesis and processing of amyloid‑β precursor protein, yielding accumulation of neurotoxic amyloid‑β[1‑42] oligomers. They may aggravate primary neurotoxic signals through interactions with extracellular and intracellular membranes and linked signal transduction [pathways. Amyloid‑β exerted no direct inhibitory effects on pyruvate dehydrogenase and other enzymes of energy and ACh metabolism. These data indicate that several cytotoxic insults may focus on acetyl-Co-A metabolism as an ultimate target linked with consecutive stages of cholinergic neurodegeneration. FINANCIAL SUPPORT: Supported by St-57 fund Medical University of Gdansk.