Wednesday, April 05, 2017 10:39:21 AM
Basic biology concepts for Alzheimer’s disease (updated 4/1/2017)
Per Amstocks82 refer questions to him please
Therefore, mitochondria need to be repaired or replaced regularly. For example, in some muscle cells such as heart tissue, mitochondria have a half life of as little as 17 days. In other words, half of the mitochondria in the heart muscle will be replaced by a new mitochondria in 17 days.
Alzheimer’s disease is physically characterized and diagnosed based on the patient having neuritic plaques and neurofibrillary tangles. Neuritic plaques are extracellular deposits of amyloid beta in the grey matter of the brain. Neurofibrillary tangles are formed by a clumping or aggregation of degraded form of the “tau protein” in an insoluble form. Alzheimer’s disease leads to a cognitive decline characterized by a loss of memory and the ability to reason.
Alzheimer’s disease is mainly a disease of the neurons. Neurons are specialized cells that are made up of three main parts: The cell body or soma, dendrites and the axon. Dendrites are extensions of the neuron that receive signals and conduct them toward the cell body. The axon is an extension of the neuron that conduct signals away from the cell body to other cells. The length of the axon may be 1,000 to even 10,000 times longer than the width of the cell body. Below are two diagrams of neurons:
A second view of a neuron:
A typical brain has over 100 billion neurons. Each individual neuron may network or form physical connections to several thousand other neurons (it is estimated that the number of connections can be up to 10,000). The number of connections in the brain could be on the order of 100 trillion to 1,000 trillion connections via a specialized connection called a synapse. The synaptic connection is typically via an axon to the dendrite of another neuron. However, some connections form between axon to axon or dendrite to dendrite.
The interaction between neurons are electrical and electro-chemical. To make this work physically, there needs to be various neurotransmitters. Those neurtransmitters are stored in the neuron and axon in organelles called "vesicles". They contain various neurotransmitters such as acetycholine, dopamine, histamine, serononin, melatonin, adrenalin and finally, the most common transmitters are glutamate and GABA. Neurons are very energy "intensive" given that a typical neuron sends an electrical or electro-chemical pulse to another neuron between 5 and 50 times per second.
The current view of Alzheimer’s disease is that there are 5 different issues most of which are interrelated:
1) Alzheimer’s patients have “amyloid plaques” located within the brain tissue. These plaques are caused by “Amyloid beta” peptides.
Amyloid beta (Aß) is defined as peptides with 36 to 43 amino acids that have been found to be the main component of the amyloid plaques found in the brains of Alzheimer patients. Proteins are also composed of amino acids. Proteins are distinguished from peptides based on size. In the older definition, a peptide usually has fewer than 50 amino acids and proteins have more than 50. Another common definition is that a protein is a stable and complete biological molecule. Usually a protein has a 3-dimensional structure. A peptide is a subset of a protein and therefore, not a complete form of the functional biological molecule and usually does not have a 3-dimensional structure.
Amyloid beta is formed when a protein called Amyloid Precursor Protein (APP) is “divided” into smaller sections. APP (Amyloid Precursor Protein) was identified due to research into amyloid beta (Aß). It is now believed that APP is used in the neurons to both form synaptic junctions and to repair them. APP is a very ancient protein that is present in several forms in all types of animal species. APP due to being an ancient protein is likely to be active in various ways other than those mentioned above. Most of which are still unknown.
APP is divided by enzymes that are called beta secretase and gamma secretase. The enzymes exist for the sole purpose of dividing or cleaving APP. Those enzymes cleave APP in ways that yield amyloid beta or Aß.
Aß molecules can aggregate to form flexible soluble oligomers (or small biological structures) which may exist in several forms. An oligomer usually refers to a macromolecular complex formed by non-covalent bonding of a few macromolecules like proteins or nucleic acids. This oligomer or macromolecular structure has a complex architecture in 3 dimensions and contain various folds and curves. To operate correctly, it must have the correct 3 dimensional form including having the various macromolecules folded correctly.
In Alzheimer’s patients, the oligomer may be “misfolded” so that it does not operate in the correct manner. The other protein implicated in Alzheimer's disease, tau protein, also forms such prion-like misfolded oligomers, and there is some evidence that misfolded Aß can induce tau to misfold.
2) Alzheimer’s patients have neurofibrillary “tangles” in their brain tissue. The tangles are associated with tau hyperphosphorylation
Tau protein is a major microtubule-associated protein (MAP) in a human brain cell or neuron. One of tau's main functions is to modulate the stability of axonal microtubules.
What are the axonal microtubules? They are major architectural (structural) elements within the neuron which allow it to maintain its shape and help to convey and aggregate materials at specific locations within the cell or neuron. Neurons have an axon and dendrites that spread out from the neuron cell body. The axon can be 1,000 to 10,000 times the length of the cell body. Given the length of the axon especially, it requires structural elements as well as some way to convey “materials” the length of the axon.
Microtubules in addition to being structural elements function like railways that convey cargo within the cell or neuron through the axon and dendrites of the neuron. The “cargo” of molecules or organelles that move along the microtubules are everything needed to maintain, provide fuel (glucose) and repair the neuron cell body, axon and dendrites. The microtubule “cargo” is also needed for such things as creating new “associations” (memories) and operating the synaptic junction. Other microtubules work in the opposite direction carrying materials in the reverse direction back from the axon or dendrite to the main neuron cell body. Microtubules are essential for moving mitochondria to where they are needed such as areas where the cell needs energy. Mitochondria move “long” distances such as within an axon or within dendrites along microtubules.
There are molecules in the neuron that regulate the activity of microtubules and how they are formed. Microtubule-associated (tau) protein (MAP) that undergoes hyperphosphorylation becomes toxic to the neuron and can lead to the death of the neuron as well as causing the neuron to operate in a less than optimum fashion. The neuron has a defense mechanism against this toxic protein. That defense mechanism degrades the hyperphosphorylated tau further into a non-toxic but inert material. If the neuron were operating efficiently, this material would get removed from the neuron over time. But if it is not working well, the inert material accumulates in the neuron and also in extracellular spaces. If sufficient of this material accumulates, it gets in the way of other cellular mechanisms effectively "clogging up" the biochemical processes of the neuron further degrading it or leading to its death.
3) Alzheimer’s patients may experience issues with calcium regulation leading to a Ca2+ imbalance. Calcium is very important and used in many ways by neurons including regulation of the activity of neurons. There are cell organelles called “calciosomes” that store and release calcium as needed. Calcium is also stored in the endoplasmic reticulum (which is a kind of assembly line that also has a structural function). There are proteins that bind with calcium in ways that help regulate it and transport it. Calcium is also stored within the mitochondria.
Mitochondria act as the cells “power plant”. Mitochondria take (fuel) food, protein, fat or glucose and convert it to the “electricity” of the cell which is a molecule called ATP that provides energy within the cell for all the various activities. The ATP changes form as it provides power from ATP to ADP and from there is typically recycled back to the mitochondria where it is “recharged” and changed back to the higher energy ATP.
Due to the fact that mitochondria provide energy, they are very active chemically, they produce more free radicals and are therefore more exposed to the damaging effect of free radicals and other substances. Due to the fact that mitochondria are subject to more damage than other organelles, they are "repaired" or replaced fairly regularly. Replacing and repairing old and damaged mitochondria is essential for maintaining cellular health.
In neurons, given the size and length of axons and dendrites, mitochondria must regularly move along the axon and dendrite to get to locations needing energy. Therefore, if the microtubules are damaged, or the cell is not operating correctly, it makes it difficult for the cell to manufacture new mitochondria to replace old ones. Old or damaged mitochondria are less efficient and produce more free radicals and ROS. This negatively impacts the health of the cells. In neurons, it is more difficult to replace mitochondria due to the fact that many are located in the periphery of the neuron – axon or dendrite. Thus, in neurons, mitochondria replacement is already slower. If something impairs the mitochondria replacement further, this degrades the ability of the neuron to function efficiently.
Cells that use a lot of energy such as certain muscle cells, organ cells such as the liver and neurons in the brain can have hundreds of mitochondria and mitochondria are an integral part of the cells “defenses” against virus and bacteria. There are various signaling mechanisms between the mitochondria, the cell nucleus and other organelles that are used to signal each other and regulate the activity of each. In fact, mitochondria are part of the "last ditch defense" of the cell. Under certain conditions, mitochondria trigger apoptosis or a type of programmed death of cells.
Viruses have co-evolved with animals and seek to take control of mitochondria activity in order to get the energy needed for viral replication and to prevent the cell from entering programmed death. If the signaling between mitochondria, the nucleus and other organelles is not working correctly, the mitochondria may not be replaced or repaired when they are damaged. Therefore, they may not provide sufficient energy. In some cases, mitochondrial damage should normally trigger cellular death but does not.
If calcium becomes deregulated, it can prevent proper functioning of the neuron and of the mitochondria. If the mitochondria are not working correctly, it is like having a power plant that is always experiencing brown outs or outages. The outages and brown outs can be very debilitating to the rest of the cell. Additionally, if the mitochondria are not operating efficiently, it produces more waste products than normal and worse waste products than normal (free radicals) and indirectly leads to the production of reactive oxygen species (ROS) which are toxic to the cell.
There are several other problems associated with calcium becoming deregulated. Basically, there are a cascade of “bad” events that can happened whenever normal calcium homeostasis is not maintained (homeostasis in this definition is the properly regulated and stable equilibrium of calcium that cells normally maintain).
4) The brain tissue of people afflicted with Alzheimer’s disease may become inflamed. Our immune cells are designed to target foreign material, viruses, germs and our own malfunctioning cells. The immune system can change the way the cells operate such that they become “hardened” against certain types of infections or even radiation damage. Additionally, cells can secrete large numbers of chemicals (inflammatory factors) that signal the immune system that damage is occurring or has occurred. This spurs the immune system to take additional actions. Such action by the immune system can cause cell deaths. Some types of cellular death spur adjoining cells to secrete even more inflammatory factors. This in turn causes the immune system to become more involved in the area. If unchecked, inflammation can spur more inflammation and more damage. Other immune cells can secrete factors that reduce inflammation and bring the damage back under control. If not brought under control, then types of autoimmune diseases can occur. In Alzheimer’s patients, inflammation can increase the damage done to the brains of people suffering from this disease.
5) People with Alzheimer’s disease are often found to have malfunctioning mitochondria. As mentioned earlier, the mitochondria act mainly as the cells power stations which provide usable energy in the form of ATP to the rest of the cell. In Alzheimer’s patients, mitochondria are often damaged or the neuron may contain too few mitochondria to match the energy expenditure needed by the cell.
Mitochondria are often depicted as round or kidney shaped organelles. Years ago, mitochondria were thought of as stable structures that live within the cell providing ATP when needed. But in modern time with better understanding of cellular activity, the understanding has changed. Mitochondria form a dynamic network within most cells where they constantly undergo fission and fusion. Mitochondria can divide in a type of binary fission where one mitochondrion divides into two. Each individual mitochondrion requires its own DNA to function. Therefore, a mitochondrion duplicates its DNA during fission. Two mitochondria can fuse together forming a longer mitochondrion. Mitochondria are somewhat “mobile” and the position of the mitochondria within the cell can change. This is very important in the axon and dendrites of the neuron given their long length. A damaged mitochondrion that is fused together with another will have duplicate DNA. If there is damaged DNA in one of the mitochondrion, the duplication allows the combined mitochondrion to work better as one of the mitochondrion genomes is not damaged.
In neurons, fusion and fission of mitochondria is more important than in other cells. In fact, neurons are unable to survive without constant change of mitochondria through fusion and fission.
The cells maintain a type of homeostasis in mitochondrial fusion and fission to maintain the amount of mitochondria needed by the cell at the location they are needed. In a cell that has “decided” to die or is dying due to being “programmed” to die (called Apoptosis), the mitochondria break down into smaller organelles. The cells essentially destroy themselves in a way that is not very destructive to surrounding cells. Mitochondria also function in close association with the cells endoplasmic reticulum. Problems with mitochondria often have a large impact on the endoplasmic reticulum or vice versa. Part of the endoplasmic reticulum membrane is closely associated with the mitochondria. This is often called Mitochondria Associated endoplasmic reticulum Membrane (MAM).
Note: "ER" refers to endoplasmic reticulum and "Mito" to mitochondrion.
Protein misfolding: The endoplasmic reticulum is very important to the folding, packaging and transport of most proteins in the cell. Ribosomes are studded in the “rough” part of the endoplasmic reticulum. Ribosomes synthesize proteins and the endoplasmic finished the process by folding them, packaging them and even “labeling” them.
The endoplasmic reticulum is in some ways like a factory that contains various things including ribosomes which are the machines in the factory that assemble parts together. This factory takes the instructions (given to it by RNA molecules that travel from the cell nucleus), and uses those instructions to create proteins, enzymes and other molecules and materials required by the cell or organism. When proteins are constructed, they may have molecules bound together sometimes in complex ways. The protein when complete is a 3D structure which can fold back in various ways. If it does not fold at the right places, the protein may have the right “formula” but not the right shape and will not work.
How does Anavex 2-73 (A2-73) help with Alzheimer’s disease?
The company writes that A2-73 is an orally available, small-molecule activator of the sigma-1 receptor restoring cellular homeostasis by targeting protein misfolding, oxidative stress, mitochondrial dysfunction, inflammation and cellular stress, factors in both neurodegenerative and neurodevelopmental diseases.
How does A2-73 accomplish this? It is a sigma-1 agonist. Due to the complexity of cellular mechanisms, the control of certain aspects of cellular activity or metabolism is controlled by signaling molecules that bind to “receptors”. An agonist is a molecule or chemical that will bind to a “receptor” in such a way that the receptor is activated triggering a biological effect. The antagonist does the opposite – binds to the receptor and blocks the biological effect. By producing agonists and antagonists that act in various ways, cellular mechanisms are controlled. Note, receptors can themselves be complex. They can be activated and deactivated in different ways triggering different reactions by different agonists and antagonists.
Sigma-1 receptors are a type of membrane protein “chaperone” that move from the MAM to the membrane of other organelles depending on the stress and the presence and types of sigma-1 receptors or agonists. Sigma-1 receptors unlike some other receptors don't have an intrinsic activity where for example, if it is activated, it takes a specific action such as to release more or less of a neurotransmitter.
As mentioned earlier, an agonist is a chemical that binds to a receptor and activates the receptor to produce a biological response. Whereas an agonist causes an action, an antagonist blocks the action of the agonist and an inverse agonist causes an action opposite to that of the agonist. The agonist and antagonist are both called “ligands”. A “chaperone” receptor such as the sigma-1 receptor is “mobile” in that it changes location due to cellular stress and the presence of ligands. In a typical cell, there might be various agonists and various antagonists for a particular receptor. There may be more than one type of agonist and more than one type of antagonist. When an agonist or antagonist binds to the receptor, it changes the 3 dimensional shape of the structure changing how it impacts various processes in the cell and even impacting where it is primarily located. Given the presence of various ligands that impact a particular receptor type, cellular interactions are complex.
Various receptors such as the sigma-1 receptor help regulate cellular processes. In particular, the sigma-1 receptor appears to have a large role in regulating “stress”. If activated in certain ways by the appropriate agonist, the sigma-1 receptor has been found to help regulate other cellular signaling molecules such as protein kinases and inositol phosphates and it helps regulate and modulate the activity of calcium channels. The regulation of those in turn impact many cellular stress related processes. Those processes influence inflammation, endoplasmic reticulum “stress” related issues such as “misfolded” protein formation and can impact the formation of Reactive Oxygen Species (ROS).
Per Amstocks82 refer questions to him please
Therefore, mitochondria need to be repaired or replaced regularly. For example, in some muscle cells such as heart tissue, mitochondria have a half life of as little as 17 days. In other words, half of the mitochondria in the heart muscle will be replaced by a new mitochondria in 17 days.
Alzheimer’s disease is physically characterized and diagnosed based on the patient having neuritic plaques and neurofibrillary tangles. Neuritic plaques are extracellular deposits of amyloid beta in the grey matter of the brain. Neurofibrillary tangles are formed by a clumping or aggregation of degraded form of the “tau protein” in an insoluble form. Alzheimer’s disease leads to a cognitive decline characterized by a loss of memory and the ability to reason.
Alzheimer’s disease is mainly a disease of the neurons. Neurons are specialized cells that are made up of three main parts: The cell body or soma, dendrites and the axon. Dendrites are extensions of the neuron that receive signals and conduct them toward the cell body. The axon is an extension of the neuron that conduct signals away from the cell body to other cells. The length of the axon may be 1,000 to even 10,000 times longer than the width of the cell body. Below are two diagrams of neurons:
A second view of a neuron:
A typical brain has over 100 billion neurons. Each individual neuron may network or form physical connections to several thousand other neurons (it is estimated that the number of connections can be up to 10,000). The number of connections in the brain could be on the order of 100 trillion to 1,000 trillion connections via a specialized connection called a synapse. The synaptic connection is typically via an axon to the dendrite of another neuron. However, some connections form between axon to axon or dendrite to dendrite.
The interaction between neurons are electrical and electro-chemical. To make this work physically, there needs to be various neurotransmitters. Those neurtransmitters are stored in the neuron and axon in organelles called "vesicles". They contain various neurotransmitters such as acetycholine, dopamine, histamine, serononin, melatonin, adrenalin and finally, the most common transmitters are glutamate and GABA. Neurons are very energy "intensive" given that a typical neuron sends an electrical or electro-chemical pulse to another neuron between 5 and 50 times per second.
The current view of Alzheimer’s disease is that there are 5 different issues most of which are interrelated:
1) Alzheimer’s patients have “amyloid plaques” located within the brain tissue. These plaques are caused by “Amyloid beta” peptides.
Amyloid beta (Aß) is defined as peptides with 36 to 43 amino acids that have been found to be the main component of the amyloid plaques found in the brains of Alzheimer patients. Proteins are also composed of amino acids. Proteins are distinguished from peptides based on size. In the older definition, a peptide usually has fewer than 50 amino acids and proteins have more than 50. Another common definition is that a protein is a stable and complete biological molecule. Usually a protein has a 3-dimensional structure. A peptide is a subset of a protein and therefore, not a complete form of the functional biological molecule and usually does not have a 3-dimensional structure.
Amyloid beta is formed when a protein called Amyloid Precursor Protein (APP) is “divided” into smaller sections. APP (Amyloid Precursor Protein) was identified due to research into amyloid beta (Aß). It is now believed that APP is used in the neurons to both form synaptic junctions and to repair them. APP is a very ancient protein that is present in several forms in all types of animal species. APP due to being an ancient protein is likely to be active in various ways other than those mentioned above. Most of which are still unknown.
APP is divided by enzymes that are called beta secretase and gamma secretase. The enzymes exist for the sole purpose of dividing or cleaving APP. Those enzymes cleave APP in ways that yield amyloid beta or Aß.
Aß molecules can aggregate to form flexible soluble oligomers (or small biological structures) which may exist in several forms. An oligomer usually refers to a macromolecular complex formed by non-covalent bonding of a few macromolecules like proteins or nucleic acids. This oligomer or macromolecular structure has a complex architecture in 3 dimensions and contain various folds and curves. To operate correctly, it must have the correct 3 dimensional form including having the various macromolecules folded correctly.
In Alzheimer’s patients, the oligomer may be “misfolded” so that it does not operate in the correct manner. The other protein implicated in Alzheimer's disease, tau protein, also forms such prion-like misfolded oligomers, and there is some evidence that misfolded Aß can induce tau to misfold.
2) Alzheimer’s patients have neurofibrillary “tangles” in their brain tissue. The tangles are associated with tau hyperphosphorylation
Tau protein is a major microtubule-associated protein (MAP) in a human brain cell or neuron. One of tau's main functions is to modulate the stability of axonal microtubules.
What are the axonal microtubules? They are major architectural (structural) elements within the neuron which allow it to maintain its shape and help to convey and aggregate materials at specific locations within the cell or neuron. Neurons have an axon and dendrites that spread out from the neuron cell body. The axon can be 1,000 to 10,000 times the length of the cell body. Given the length of the axon especially, it requires structural elements as well as some way to convey “materials” the length of the axon.
Microtubules in addition to being structural elements function like railways that convey cargo within the cell or neuron through the axon and dendrites of the neuron. The “cargo” of molecules or organelles that move along the microtubules are everything needed to maintain, provide fuel (glucose) and repair the neuron cell body, axon and dendrites. The microtubule “cargo” is also needed for such things as creating new “associations” (memories) and operating the synaptic junction. Other microtubules work in the opposite direction carrying materials in the reverse direction back from the axon or dendrite to the main neuron cell body. Microtubules are essential for moving mitochondria to where they are needed such as areas where the cell needs energy. Mitochondria move “long” distances such as within an axon or within dendrites along microtubules.
There are molecules in the neuron that regulate the activity of microtubules and how they are formed. Microtubule-associated (tau) protein (MAP) that undergoes hyperphosphorylation becomes toxic to the neuron and can lead to the death of the neuron as well as causing the neuron to operate in a less than optimum fashion. The neuron has a defense mechanism against this toxic protein. That defense mechanism degrades the hyperphosphorylated tau further into a non-toxic but inert material. If the neuron were operating efficiently, this material would get removed from the neuron over time. But if it is not working well, the inert material accumulates in the neuron and also in extracellular spaces. If sufficient of this material accumulates, it gets in the way of other cellular mechanisms effectively "clogging up" the biochemical processes of the neuron further degrading it or leading to its death.
3) Alzheimer’s patients may experience issues with calcium regulation leading to a Ca2+ imbalance. Calcium is very important and used in many ways by neurons including regulation of the activity of neurons. There are cell organelles called “calciosomes” that store and release calcium as needed. Calcium is also stored in the endoplasmic reticulum (which is a kind of assembly line that also has a structural function). There are proteins that bind with calcium in ways that help regulate it and transport it. Calcium is also stored within the mitochondria.
Mitochondria act as the cells “power plant”. Mitochondria take (fuel) food, protein, fat or glucose and convert it to the “electricity” of the cell which is a molecule called ATP that provides energy within the cell for all the various activities. The ATP changes form as it provides power from ATP to ADP and from there is typically recycled back to the mitochondria where it is “recharged” and changed back to the higher energy ATP.
Due to the fact that mitochondria provide energy, they are very active chemically, they produce more free radicals and are therefore more exposed to the damaging effect of free radicals and other substances. Due to the fact that mitochondria are subject to more damage than other organelles, they are "repaired" or replaced fairly regularly. Replacing and repairing old and damaged mitochondria is essential for maintaining cellular health.
In neurons, given the size and length of axons and dendrites, mitochondria must regularly move along the axon and dendrite to get to locations needing energy. Therefore, if the microtubules are damaged, or the cell is not operating correctly, it makes it difficult for the cell to manufacture new mitochondria to replace old ones. Old or damaged mitochondria are less efficient and produce more free radicals and ROS. This negatively impacts the health of the cells. In neurons, it is more difficult to replace mitochondria due to the fact that many are located in the periphery of the neuron – axon or dendrite. Thus, in neurons, mitochondria replacement is already slower. If something impairs the mitochondria replacement further, this degrades the ability of the neuron to function efficiently.
Cells that use a lot of energy such as certain muscle cells, organ cells such as the liver and neurons in the brain can have hundreds of mitochondria and mitochondria are an integral part of the cells “defenses” against virus and bacteria. There are various signaling mechanisms between the mitochondria, the cell nucleus and other organelles that are used to signal each other and regulate the activity of each. In fact, mitochondria are part of the "last ditch defense" of the cell. Under certain conditions, mitochondria trigger apoptosis or a type of programmed death of cells.
Viruses have co-evolved with animals and seek to take control of mitochondria activity in order to get the energy needed for viral replication and to prevent the cell from entering programmed death. If the signaling between mitochondria, the nucleus and other organelles is not working correctly, the mitochondria may not be replaced or repaired when they are damaged. Therefore, they may not provide sufficient energy. In some cases, mitochondrial damage should normally trigger cellular death but does not.
If calcium becomes deregulated, it can prevent proper functioning of the neuron and of the mitochondria. If the mitochondria are not working correctly, it is like having a power plant that is always experiencing brown outs or outages. The outages and brown outs can be very debilitating to the rest of the cell. Additionally, if the mitochondria are not operating efficiently, it produces more waste products than normal and worse waste products than normal (free radicals) and indirectly leads to the production of reactive oxygen species (ROS) which are toxic to the cell.
There are several other problems associated with calcium becoming deregulated. Basically, there are a cascade of “bad” events that can happened whenever normal calcium homeostasis is not maintained (homeostasis in this definition is the properly regulated and stable equilibrium of calcium that cells normally maintain).
4) The brain tissue of people afflicted with Alzheimer’s disease may become inflamed. Our immune cells are designed to target foreign material, viruses, germs and our own malfunctioning cells. The immune system can change the way the cells operate such that they become “hardened” against certain types of infections or even radiation damage. Additionally, cells can secrete large numbers of chemicals (inflammatory factors) that signal the immune system that damage is occurring or has occurred. This spurs the immune system to take additional actions. Such action by the immune system can cause cell deaths. Some types of cellular death spur adjoining cells to secrete even more inflammatory factors. This in turn causes the immune system to become more involved in the area. If unchecked, inflammation can spur more inflammation and more damage. Other immune cells can secrete factors that reduce inflammation and bring the damage back under control. If not brought under control, then types of autoimmune diseases can occur. In Alzheimer’s patients, inflammation can increase the damage done to the brains of people suffering from this disease.
5) People with Alzheimer’s disease are often found to have malfunctioning mitochondria. As mentioned earlier, the mitochondria act mainly as the cells power stations which provide usable energy in the form of ATP to the rest of the cell. In Alzheimer’s patients, mitochondria are often damaged or the neuron may contain too few mitochondria to match the energy expenditure needed by the cell.
Mitochondria are often depicted as round or kidney shaped organelles. Years ago, mitochondria were thought of as stable structures that live within the cell providing ATP when needed. But in modern time with better understanding of cellular activity, the understanding has changed. Mitochondria form a dynamic network within most cells where they constantly undergo fission and fusion. Mitochondria can divide in a type of binary fission where one mitochondrion divides into two. Each individual mitochondrion requires its own DNA to function. Therefore, a mitochondrion duplicates its DNA during fission. Two mitochondria can fuse together forming a longer mitochondrion. Mitochondria are somewhat “mobile” and the position of the mitochondria within the cell can change. This is very important in the axon and dendrites of the neuron given their long length. A damaged mitochondrion that is fused together with another will have duplicate DNA. If there is damaged DNA in one of the mitochondrion, the duplication allows the combined mitochondrion to work better as one of the mitochondrion genomes is not damaged.
In neurons, fusion and fission of mitochondria is more important than in other cells. In fact, neurons are unable to survive without constant change of mitochondria through fusion and fission.
The cells maintain a type of homeostasis in mitochondrial fusion and fission to maintain the amount of mitochondria needed by the cell at the location they are needed. In a cell that has “decided” to die or is dying due to being “programmed” to die (called Apoptosis), the mitochondria break down into smaller organelles. The cells essentially destroy themselves in a way that is not very destructive to surrounding cells. Mitochondria also function in close association with the cells endoplasmic reticulum. Problems with mitochondria often have a large impact on the endoplasmic reticulum or vice versa. Part of the endoplasmic reticulum membrane is closely associated with the mitochondria. This is often called Mitochondria Associated endoplasmic reticulum Membrane (MAM).
Note: "ER" refers to endoplasmic reticulum and "Mito" to mitochondrion.
Protein misfolding: The endoplasmic reticulum is very important to the folding, packaging and transport of most proteins in the cell. Ribosomes are studded in the “rough” part of the endoplasmic reticulum. Ribosomes synthesize proteins and the endoplasmic finished the process by folding them, packaging them and even “labeling” them.
The endoplasmic reticulum is in some ways like a factory that contains various things including ribosomes which are the machines in the factory that assemble parts together. This factory takes the instructions (given to it by RNA molecules that travel from the cell nucleus), and uses those instructions to create proteins, enzymes and other molecules and materials required by the cell or organism. When proteins are constructed, they may have molecules bound together sometimes in complex ways. The protein when complete is a 3D structure which can fold back in various ways. If it does not fold at the right places, the protein may have the right “formula” but not the right shape and will not work.
How does Anavex 2-73 (A2-73) help with Alzheimer’s disease?
The company writes that A2-73 is an orally available, small-molecule activator of the sigma-1 receptor restoring cellular homeostasis by targeting protein misfolding, oxidative stress, mitochondrial dysfunction, inflammation and cellular stress, factors in both neurodegenerative and neurodevelopmental diseases.
How does A2-73 accomplish this? It is a sigma-1 agonist. Due to the complexity of cellular mechanisms, the control of certain aspects of cellular activity or metabolism is controlled by signaling molecules that bind to “receptors”. An agonist is a molecule or chemical that will bind to a “receptor” in such a way that the receptor is activated triggering a biological effect. The antagonist does the opposite – binds to the receptor and blocks the biological effect. By producing agonists and antagonists that act in various ways, cellular mechanisms are controlled. Note, receptors can themselves be complex. They can be activated and deactivated in different ways triggering different reactions by different agonists and antagonists.
Sigma-1 receptors are a type of membrane protein “chaperone” that move from the MAM to the membrane of other organelles depending on the stress and the presence and types of sigma-1 receptors or agonists. Sigma-1 receptors unlike some other receptors don't have an intrinsic activity where for example, if it is activated, it takes a specific action such as to release more or less of a neurotransmitter.
As mentioned earlier, an agonist is a chemical that binds to a receptor and activates the receptor to produce a biological response. Whereas an agonist causes an action, an antagonist blocks the action of the agonist and an inverse agonist causes an action opposite to that of the agonist. The agonist and antagonist are both called “ligands”. A “chaperone” receptor such as the sigma-1 receptor is “mobile” in that it changes location due to cellular stress and the presence of ligands. In a typical cell, there might be various agonists and various antagonists for a particular receptor. There may be more than one type of agonist and more than one type of antagonist. When an agonist or antagonist binds to the receptor, it changes the 3 dimensional shape of the structure changing how it impacts various processes in the cell and even impacting where it is primarily located. Given the presence of various ligands that impact a particular receptor type, cellular interactions are complex.
Various receptors such as the sigma-1 receptor help regulate cellular processes. In particular, the sigma-1 receptor appears to have a large role in regulating “stress”. If activated in certain ways by the appropriate agonist, the sigma-1 receptor has been found to help regulate other cellular signaling molecules such as protein kinases and inositol phosphates and it helps regulate and modulate the activity of calcium channels. The regulation of those in turn impact many cellular stress related processes. Those processes influence inflammation, endoplasmic reticulum “stress” related issues such as “misfolded” protein formation and can impact the formation of Reactive Oxygen Species (ROS).
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