Aluminum, NO, and nerve growth factor neurotoxicity in cholinergic neurons

Abstract

Several neurotoxic compounds, including Al, NO, and beta-amyloid may contribute to the impairment or loss of brain cholinergic neurons in the course of various neurodegenerative diseases. Genotype and phenotypic modifications of cholinergic neurons may determine their variable functional competency and susceptibility to reported neurotoxic insults. Hybrid, immortalized SN56 cholinergic cells from mouse septum may serve as a model for in vitro cholinotoxicity studies. Differentiation by various combinations of cAMP, retinoic acid, and nerve growth factor may provide cells of different morphologic maturity as well as activities of acetylcholine and acetyl-CoA metabolism. In general, differentiated cells appear to be more susceptible to neurotoxic signals than the non-differentiated ones, as evidenced by loss of sprouting and connectivity, decreases in choline acetyltransferase and pyruvate dehydrogenase activities, disturbances in acetyl-CoA compartmentation and metabolism, insufficient or excessive acetylcholine release, as well as increased expression of apoptosis markers. Each neurotoxin impaired both acetylcholine and acetyl-CoA metabolism of these cells. Activation of p75 or trkA receptors made either acetyl-CoA or cholinergic metabolism more susceptible to neurotoxic influences, respectively. Neurotoxins aggravated detrimental effects of each other, particularly in differentiated cells. Thus brain cholinergic neurons might display a differential susceptibility to Al and other neurotoxins depending on their genotype or phenotype-dependent variability of the cholinergic and acetyl-CoA metabolism.

Memory performance, brain excitatory amino acid and acetylcholinesterase activity of chronically aluminum exposed mice in response to soy isoflavones treatment

“…The SI effect on learning and memory ability of chronically Al exposed animals might be related to their antioxidative function. Considerable evidence has demonstrated that chronic Al exposure caused the dysfunction of several neurotransmitter enzymes, including choline acetyl transferase (ChAT), acetylcholinesterase (AChE) (Bielarczyk et al, 1998;Szutowicz, 2001) and glutamate α-decarboxylase (Nayak and Chatterjee, 2001). Al exposure also altered the concentrations of amino acid neurotransmitters, their metabolites in several brain regions (Beal et al, 1989;Jia et al, 2001).…”

Acetyl-CoA the Key Factor for Survival or Death of Cholinergic Neurons in Course of Neurodegenerative Diseases

“…They include: Aβ 1–42 accumulation, excitotoxicity/NO excess, mitochondrial dysfunction, hypoxia/anoxia/hypoglycaemia, oxygen radicals formation, inflammation, metals (Ca 2+ , Zn 2+ , Fe 2+ , Al 3+ ) accumulation, or neurothrophin depletion, which were investigated as cytotoxic signals in AD (Fig. 2) [27, 90, 91, 93, 94, 112–118]. Also activation of microglia yielding increased release of proinflamatory interleukins may induce neurodegeneration through Wnt or p75 neurotrophin receptor-dependent signal transduction pathways [75, 119, 120].…”

“…Most of these cytotoxic signals directly affected activities of enzymes linked with energy and acetyl-CoA metabolism in humans as well as animal and cellular models of AD [13, 27, 96, 102, 104, 118]. …”

Does neurotransmission impairment accompany aluminium neurotoxicity?

“…Selective lost of cholinergic [86], GABAergic [246] and nitroxidergic [247] neurons in response to exposure to aluminium has been reported. Furthermore, alteration of nerve cell morphology is a common feature of aluminium neurotoxicity.…”