Amyloid beta Amyloid beta (Aβ) was found to cause neurotoxicity and cell death in the brain when present in high concentrations. Aβ results from a mutation that occurs when protein chains are cut at the wrong locations, resulting in chains of different lengths that are unusable. Thus they are left in the brain until they are broken down, but if enough accumulate, they form
plaques which are toxic to
neurons. Aβ uses several routes in the
central nervous system 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 causes cell death is through the
phosphorylation of
AKT; this occurs as the phosphate group 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 extremely delicate and is usually found in millimolar amounts extracellularly. When disturbed, an accumulation of glutamate occurs as a result of a mutation in the
glutamate transporters, which act like pumps to clear glutamate from the synapse. This causes glutamate concentration to be 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 neurons of the brain. In the event of a mutation, the glutamate transporters are unable to pump the glutamate back into the cells; thus a higher concentration accumulates at the
glutamate receptors. This opens the ion channels, allowing calcium to enter the cell causing excitotoxicity. Glutamate results in cell death by turning on the
N-methyl-D-aspartic acid receptors (NMDA); these receptors cause an increased release of calcium ions (Ca2+) into the cells. 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 a brain 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 break down 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 than other organs, due to its low oxidative capacity. Because
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.
Dopaminergic Neurotoxicity Endogenous The endogenously produced autotoxin metabolite of dopamine,
3,4-Dihydroxyphenylacetaldehyde (DOPAL), is a potent inducer of
programmed cell death (apoptosis) in dopaminergic neurons. DOPAL may play an important role in the pathology of
Parkinson's disease.
Drug induced Certain drugs, most famously the
pesticide and metabolite
MPP+ (1-methyl-4-phenylpyridin-1-ium) can induce
Parkinson's disease by destroying dopaminergic neurons in the
substantia nigra. MPP+ is produced by
monoamine oxidase B as a metabolite of
MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), and its toxicity is particularly significant to dopaminergic neurons because of an
active transporter on those cells that bring it into the cytoplasm. Discovery of the mechanism of toxicity was an important advance in the study of Parkinson's disease, and the compound is now used to induce the disease in research animals. ==Prognosis==