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Some of the most common naturally occurring brain toxins that lead to neurotoxicity as a result of excessive dosage are: Beta amyloid (Aβ), Glutamate and Oxygen radicals. When present in high concentrations they can lead to neurotoxicity and death (apoptosis). Some of the symptoms that result from cell death include: loss of motor control, cognitive deterioration and autonomic nervous system dysfunction. Additionally, neurotoxicity has been found to be a major cause of neurodegenerative diseases such as Alzheimer’s disease (AD).

Beta amyloid
Aβ was found to cause neurotoxicity and cell death in the brain when found in high concentrations. Aβ results from a mutation that occurs when protein chains are cut at wrong locations, resulting in chains of different length that are unusable. Thus they are left in the brain until they are broken down, but meanwhile if enough accumulate, they form plaques which are regarded toxic to neurons. Aβ uses several routes in the CNS to cause cell death. An example is through the nicotinic acetylcholine receptor (nAchRs), which is a receptor commonly found along the surfaces of the cells that respond to nicotine stimulation, turning them on or off. Aβ was found manipulating the level of nicotine in the brain along with the MAP kinase, another signaling receptor, to cause cell death. Another chemical in the brain that Aβ regulates is JNK; this chemical halts the extracellular signal-regulated kinases (ERK) pathway, which normally functions as memory control in the brain. As a result this memory favoring pathway is stopped and the brain loses essential memory function. The loss of memory is a symptom of neurodegenerative disease, including AD. Another way Aβ cause cell death is through the phosphorylation of AKT, this occurs as the element phosphate is bound to several sites on the protein. This phosphorylation allows AKT to interact with BAD, a protein known to cause cell death. Thus an increase in Aβ results in an increase of the AKt/BAD complex, in turn stopping the action of the anti-apoptotic protein Bcl-2, which normally functions to stop cell death, causing accelerated neuron breakdown and the progression of AD.

Glutamate
Glutamate is a chemical found in the brain that poses a toxic threat to neurons when found in high concentrations. This concentration equilibrium is highly sensitive, and it’s usually found in millimolar amounts in the brain. When disturbed, an accumulation of glutamate occurs as a result of a mutation in the glutamate transporters, which act like pumps to drain glutamate from the brain. Naturally, glutamate concentration is several times higher in the blood than in the brain; in turn the body must act to maintain equilibrium between the two concentrations by pumping the glutamate out of the bloodstream and into the brain and vice versa. In the event of a mutation, the glutamate transporters are unable to pump back the glutamate into the blood; thus a higher concentration accumulates in the brain. When released it acts on several receptors that translate its release into an increase in calcium production. Glutamate results in cell death by turning on the N-methyl-D-aspartic acid receptors (NMDA); this receptor causes an increased release of calcium ions (Ca2+) into the cell. As a result, the increased concentration of Ca2+ directly increases the stress on mitochondria, resulting in excessive oxidative phosphorylation and production of Reactive Oxygen Species (ROS) via the activation of nitric oxide synthase, ultimately leading to cell death. Aβ was also found aiding this route to neurotoxicity by enhancing neuron vulnerability to glutamate.

Oxygen radicals
The formation of oxygen radicals in the brain is achieved through the nitric oxide synthase (NOS) pathway. This reaction occurs as a response to an increase in the Ca2+ concentration inside of the cell. This interaction between the Ca2+ and NOS results in the formation of the cofactor tetrahydrobiopterin (BH4), which then moves from the plasma membrane into the cytoplasm. As a final step, NOS is dephosphorylated yielding nitric oxide (NO), which accumulates in the brain, increasing its oxidative stress. There are several ROS including: superoxide, hydrogen peroxide and hydroxyl, all of which lead to neurotoxicity. Naturally, the body utilizes a defensive mechanism to diminish the fatal effects of the reactive species by employing certain enzymes to breakdown the ROS into small, benign molecules of simple oxygen and water. However, this breakdown of the ROS is not completely efficient; some reactive residues are left in the brain to accumulate, contributing to neurotoxicity and cell death. The brain is more vulnerable to oxidative stress, in comparison to other organs, due to its low oxidative capacity. Since neurons are characterized as postmitotic cells, meaning that they live with accumulated damage over the years, accumulation of ROS is fatal. Thus, increased levels of ROS age neurons, which leads to accelerated neurodegenerative processes and ultimately the advancement of AD.