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

Abstract

There are several systemic and intracerebral pathologic conditions, which limit provision and utilization of energy precursor metabolites in neuronal cells. Energy deficits cause excessive depolarization of neuronal cells triggering glutamate-zinc evoked excitotoxic cascade. The intracellular zinc excess hits several intraneuronal targets yielding collapse of energy balance and impairment functional and structural impairments cholinergic neurons. Disturbances in metabolism of acetyl-CoA, which is a direct precursor for energy, acetylcholine, N-acetyl-l-aspartate and acetylated proteins synthesis, play an important role in these pathomechanisms. Disruption of brain homeostasis activates slow accumulation of amyloid-β1−42, which extra and intracellular oligomeric deposits disrupt diverse transporting and signaling processes in all membrane structures of the cell. Both neurotoxic signals may combine aggravating detrimental effects on neuronal cell. Different neuroglial and neuronal cell types may display differential susceptibility to similar pathogenic insults depending on specific features of their energy and functional parameters. This review, basing on findings gained from cellular and animal models of Alzheimer’s disease, discusses putative energy/acetyl-CoA dependent mechanism in early and late stages of neurodegeneration.

The Regulatory Effects of Acetyl-CoA Distribution in the Healthy and Diseased Brain

“…Therefore, in ketonemic conditions these ketoacids may became a significant precursor of intramitochondrial acetyl-CoA in non-neuronal cellular compartments of the brain. These data indicate that irrespective of origin, acetyl-CoA is a central point of energy metabolism in cell mitochondria and a primary precursor for multiple synthetic and signaling pathways in various extramitochondrial compartments ( Szutowicz et al, 2013 , 2017 ).…”

“…The maintenance of this basal neuronal function requires marked energy expenses for the restoration of membrane potential and preservation of the stable neurotransmitter pool in synaptic vesicles. Therefore, neurons are more susceptible than glial cells to diverse range pathologic inputs that limit the supply of oxygen and/or glucose and lactate as principal energy substrates ( Szutowicz et al, 2013 , 2017 ).…”

“…The level of acetyl-CoA in every cell type, including neurons and neuroglia, is resultant of rates of its synthesis and utilization within mitochondria and outward transport for consumption in a broad range of synthetic pathways taking place in extramitochondrial compartments ( Szutowicz et al, 1996 , 2013 , 2017 ; Kouzarides, 2000 ; Pietrocola et al, 2015 ; Drazic et al, 2016 ).…”

“…Several reports indicate that shifts in cellular compartmentation and rates of metabolism of direct energy precursors such as pyruvate/lactate and its conversion to acetyl-CoA by PDHC may take part in the adaptative processes during brain maturation, aging, and diverse neuropathophysiological conditions ( Halim et al, 2010 ; Jha et al, 2016 ). Hence, acetyl-CoA as an immediate substrate for TCA and diverse key acetylation reactions should be considered as one of the key regulatory signals in these conditions ( Szutowicz et al, 2013 , 2017 ; Pietrocola et al, 2015 ; Peng et al, 2016 ).…”

Profiling donepezil template into multipotent hybrids with antioxidant properties

“…To supplement therapeutic profile, the metal-chelating properties of 19 towards selected biometals like Cu(II), Fe (II), and Zn (II), were inspected. The latter might prevent from the slow accumulation of Aβ 42 and thus impede its precipitation and crosslinking 99 . Indeed, compound 19 displayed 1:1 stoichiometry with Cu(II) thus could provide positive outcome likewise clioquinol or PBT2 100 , 101 .…”