College of Medicine Class of 2004
Medical University of South Carolina
summary | neurofibrillary tangles-the tau protein | inflammatory response | beta amyloid plaques
College of Medicine Class of 2004
Medical University of South Carolina
summary | neurofibrillary tangles-the tau protein | inflammatory response | beta amyloid plaques
Alzheimer’s Disease (AD) is a neurodegenerative disorder which attacks nerve cells in the cortex of the brain. It leads to impairment of emotional control, coordination, loss of bodily functions and memory and eventually death (MDConsult, 2000, Fine, 1999). It is estimated that 50% of the people over 85 years old have AD and that it is the forth leading cause of death in adults. While great strides in Alzheimer’s Disease research has taken place over the last decade, the "neuropathology of Alzheimer’s Disease remains hazy and patchy" and the "dramatic accumulation of data does not clarify the confusing picture of Alzheimer’s Disease" (Drouet, et. al., 2000).
Unfortunately, Alzheimer’s Disease is a difficult one to diagnose, treat, and plan for. These difficulties arise from Alzheimer’s being a "complex" disorder of "independent contributions or synergistic interactions of one or more genes and environmental risk factors" (Mayeux, 1998). Ashall, 1995, concurred when he stated that Alzheimer’s Disease was a "heterogeneous group of dementing illnesses that share several common clinical and pathological landmarks" with "considerable phenotypic and genotypic heterogeneity." All this means that Alzheimer’s Disease is difficult to characterize in terms of risk factors and common disease pathways between patients, which leads to difficulty diagnosing and treating Alzheimer’s Disease patients.
There are some common pathological hallmarks of Alzheimer’s Disease. They are 1) the presence of senile plaques of beta-amyloid in certain brain regions, 2) neurofibrillary tangles composed primarily of hyperphosphorylated tau proteins, and 3) the loss of synapses in the nervous system (Butterfield, et. al., 1997). However, some of these occurrences are natural and are found in the brains of non-Alzheimer’s people. Hindering strides in the research of Alzheimer’s Disease is the lack of knowledge of the normal function of many of the substances and pathways evident in the disease progression. These include the Amyloid Precursor Protein (APP), presenilin proteins, tau proteins, and apolipoprotein E (Apo E) (Drouet, et. al., 2000). Genetic and environmental factors may contribute to problems in one or more of the above substances. There are also two named types of Alzheimer’s Disease, either familial or sporadic, with familial being the more genetic inherited one and sporadic occurring in patients without a family history of the disease. Alzheimer’s can be further characterized by Early Onset (symptoms first appearing age less than 60) and Late Onset (symptoms first appearing age greater than 60). There is also some disagreement among researchers as to what the main cause of Alzheimer’s is, with either tau hyperphosphorylation the starting point or beta-amyloid plaque buildup. However, both lead to an inflammatory process after the initial trigger with oxidative damage following and cell death (Hurley, et. al., 1999).
The following review will discuss and explain some of the biochemical markers and problems associated with Alzheimer’s Disease. The neurofibrillary tangles, tau protein, beta-amyloid plaques, genetic factors, and inflammatory/oxidative free radical problems will be discussed. Alzheimer’s Disease is a rapidly advancing area of biomedical research with new pieces of the puzzle being added daily, weekly, monthly and yearly. While these advances may seem slow to patients currently suffering from this disease, it does lend hope for the future. Alzheimer’s Disease research has made great strides in the past decade. However, much more needs to be done. Unfortunately the multiple causes of Alzheimer’s Disease make it a difficult one to diagnose, treat, and predict or prevent.
Neurofibrillary tangles are twisted nerve cell fibers. They are made up of the damaged remains of microtubles-the support structure of the cell (MDConsult, 2000). Microtubules aid in cell structure and in movement and anchoring of various cell bodies. Tau proteins aid in cell microtubule assembly. The tau protein interacts with cytoskeletal proteins actin and alpha-spectrin which also aid in cytoskeletal maintenance and trafficking (Drouet, et. al., 2000). The protein helps microtubule assembly by promoting tubulin polymerization and reducing dynamic instability of the microtubule. This binding of tau protein increases the rate of association at the end of the microtubule and decreases the rate of dissociation at the growing end (Godert, et. al., 1997). The tau protein thus promotes microtubule stability and by extension cell stability.
However, problems arise when the tau becomes hyperphosphorylated at the serine and threonine residues of the protein by a still unknown mechanism (Tanaka, et. al., 2000). These abnormal tau proteins may inhibit normal tau binding to microtubules (Goedert, et. al., 1997). Hyperphosphorylated tau protein loses its ability to bind tubulin and stabilize microtubule assembly (Drouet, et. al., 2000). This loss of binding causes microtubule breakdown into paired helical filaments (PHFs) and neurofibrillary tangles-one of the indicators of Alzheimer’s Disease. However, the "exact role of tangles in the development of Alzheimer’s Disease is unclear and controversial" (Drouet, et. al., 2000).
See Klatt, E.
The "neurofibrillary tangles of paired helical filaments of broken down microtubules are neuropathologic hallmarks of Alzheimer’s Disease and abnormally hyperphosphorylated tau protein is the major protein subunit of PHF’s" (Tanaka, et. al., 2000). Exactly how these filaments affect the cell is unknown but they may lead to neuron death (Fine, 1999). Tau has been shown to be a major component of these paired helical filaments and may even cause them (Lee, et. al., 1991). The exact method by which tau forms the PHF’s is unknown, however. Tanaka, et. al., 2000, states that glycogen synthase kinase-3 may be the major phosphorylator of tau residues and Goedert, et. al., 1997 states that it may be a MAP kinase. Hopefully this indecision will be resolved by further research.
Tau protein has also been investigated as a possible marker or diagnostic factor for Alzheimer’s Disease. Meccocci, et. al., 1998, stated that tau levels were raised in the cerebrospinal fluid of Alzheimer’s patients. They also found higher levels in late onset Alzheimer’s patients versus early onset. While the origin of the tau protein in the cerebrospinal fluid was unclear, it is a promising advance in finding a physiological diagnostic marker for Alzheimer’s.
Illenberger, et. al., 1998, found that tau was phosphorylated normally during mitosis-especially metaphase. This would contribute to cell division by breaking down the microtubules which normally aid in cytoskeletal structure. It was further conjectured that the hyperphosphorylation of tau in Alzheimer’s patients may be the result of neuronal cells trying to reenter the cell cycle, something they should not do. This attempt leads to neuron death by breaking down the microtubules while the rest of the cell remains normal (non-mitotic) and having them reform into paired helical filaments.
As a final note there has been no difference shown between the neurofibrillary tangle densities in familial versus sporadic Alzheimer’s Disease patients (Lippa, et. al., 1996). This shows a common link between these two types of Alzheimer’s Disease. The genetics of Alzheimer’s Disease is further discussed in the Genetics section.
The beta-amyloid plaque formation seen in Alzheimer’s Disease begins with Amyloid Precursor Protein (APP). While the physiologic functions of APP are not fully known (Takahashi, et. al., 2000), it may play a role in nerve cell protection (MDConsult, 2000) or have a growth promoting effect (Wasco, et. al., 1997). Mattson, et. al., 1993 stated that secreted APP may help protect cells from the toxic affects of glutamate (toxic to nerve cells) and by regulating intracellular calcium levels. Much more information and research needs to be gathered on the normal physiologic function of the APP protein. The APP protein has multiple integral membrane sites and can become cleaved at various points to form the beta-amyloid peptide. The beta-amyloid peptide is approximately 39-43 amino acids long with 28 extracellular and 11-15 transmembrane amino acid long regions (Fine, 1999).
Presenilins are either the protein which regulates the enzyme or the enzyme itself which cleaves the APP to form the beta-amyloid subunit (MDConsult, 2000). This protein comes in two forms, presenilin-1 (PS-1) and presenilin-2 (PS-2), and mutations in this protein have been implicated in Alzheimer’s Disease. The mutations will be discussed further in the genetics section. The exact mechanism by which beta-amyloid forms plaques in the neurons is unknown but they are either one of the indicators or consequences of Alzheimer’s Disease.
See Klatt E.
These beta-amyloid fragments of APP form plaques on the outside of neurons. These plaques build up and eventually contribute in some way to cell death. However, "the factors responsible for inducing aggregation of the peptide have yet to be established" (Drouet, et. al., 2000). Further complicating the picture is the finding that beta-amyloid plaques are found in the normal brains of non-demented elderly individuals and that there is no strong evidence pointing to beta-amyloid plaques being toxic themselves (Drouet, et. al., 2000). However, there seems to be a myriad of secondary results of beta-amyloid plaque formation. These plaques may disrupt sodium, potassium and calcium channels of the neuron and lead to ion imbalances and interfere with nerve cell function and signal transmission (MDConsult, 2000). Other mechanisms proposed for how the plaques produce cell death include intracellular calcium accumulation, nitric oxide and peroxide production (reactive oxygen species, see Inflammatory Response section), membrane lipid peroxidation, decreased membrane fluidity, and alteration of the cytoskeleton and nucleus of the neuronal cell. All of these contribute to necrosis or apoptosis (death) of the cell (Drouet, et. al., 2000). While the reactive oxygen species formed will be discussed further later, their formation may be a secondary event of beta-amyloid induced cell death resulting in a cascade effect leading to the greater accumulation of beta-amyloid plaques on other neurons, their death and so forth. In fact the beta-amyloid cascade hypothesis, while accepted by some, is not a universal belief in the cause of Alzheimer’s Disease (Fine, 1999).
Another affect of high beta-amyloid peptides is the association with decreased levels of acetylcholine, a neurotransmitter. Acetylcholine is essential for memory and learning, two deficits seen in Alzheimer’s Disease patients (MDConsult, 2000). It is unknown however, whether the reduced acetylcholine is a secondary result of nerve cell death and fewer nerve cells or if it is somehow inhibited by the pathology of the disease.
Oxidative stress plays an important role in Alzheimer’s Disease. One of the consequences of the beta-amyloid plaques is free radical formation. The beta-amyloid plaques may break into fragments, which release oxygen free radicals. While free radical formation is a normal bodily function, there are numerous mechanisms for getting rid of them, including glutathione peroxidase and catalayse enzymes. These free radicals can be harmful to a cell if allowed to persist for a long time or in high numbers. The free radicals may bind to other molecules in the body and damage them (MDConsult, 2000, Rottkamp, et. al., 2000). The free radicals derived from beta-amyloid can bind to membrane lipids, proteins, and the nucleic acids of DNA and damage them (Butterfield, et. al., 1997). The Amyloid Precursor Protein discussed in the previous section can bind to heme oxygenase (HO) and inhibit the HO activity. HO aids antioxidant activity by breaking down heme to biliverdin which is converted to bilirubin, which has antioxidant activity. Bilirubin also aids in getting rid of iron stores which can affect the conversion of H2O2 to OH radical (Takahashi, et. al., 2000). Iron is also increased in beta-amyloid lesions (Rottkamp, et. al., 2000). The HO-1 protein is the most sensitive indicator of cellular oxidative stress response from free radicals and this protein and the mRNA which codes for it are both raised in Alzheimer’s Disease (Rottkamp, et. al., 2000). Where research along these lines will proceed is unknown.
There is also a possible therapeutic affect of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in Alzheimer’s Disease. These drugs block cyclooxygenase activity. Cyclooxygenase breaks down arachidonic acid to prostaglandins and thromboxanes, compounds instrumental in the body’s reaction to damage. Currently however, there has not been a link established between higher cyclooxygenase activity and Alzheimer’s Disease. There is a higher incidence of free radical prostaglandin isomers however (Montine, et. al., 1999). There may be a future in using NSAIDs in treatment and prevention of Alzheimer’s Disease but currently that link has not been established. The increased levels of prostaglandins may also increase the levels of glutamate. This amino acid is a "powerful nerve-cell killer" (MDConsult, 2000). The reduction of glutamate by NSAIDs reducing the amount of prostaglandins produced may be an added benefit of NSAID treatment.
Many of the indicators of Alzheimer’s Disease discussed in other sections can be traced back to genetic factors, either mutations in genes or proteins or inheriting genes which increase the risk of Alzheimer’s Disease. One of the markers for late onset and familial Alzheimer’s Disease is an allele of apolipoprotein E (Apo E). This protein has a role in movement and distribution of cholesterol for repairing nerve cells and is found primarily in high density lipoprotein (HDL) (Fine, 1999) as well as chylomicrons and very low density lipoprotein (VLDL) and in thought to be mediator of interaction between these lipoprotein transporters and lipoprotein receptors (Mulder, et. al., 1998). There are currently three alleles or different genes for coding Apo E, and one is inherited from each parent. They are Apo E2, Apo E3, and Apo E4. These alleles are extremely similar and differ in only one or two amino acid resides from each other. Apo E2 differs from Apo E3 by a cysteine for arginine substitution at residue 158 while Apo E4 differs from Apo E3 by and arginine for cysteine substitution at residue 112 (Mulder, et. al., 1997). The highest level of beta-amyloid plaque formation is seen in patients with two copies of the Apo E4 gene, less in those with one or the Apo E3 gene and fewest in those with the Apo E2 gene. If two copies of Apo E4 are present then the patient is 10 times more likely to develop Alzheimer’s Disease while one copy confers 2-3 times the risk (Fine, 1999). It is thought that Apo E4 and Apo E3 may induce and inflammatory response in the brain while Apo E2 has possible protective qualities (MDConsult, 2000). All of this is supposition right now as more needs to be discovered on the specific role and effects of these different alleles on neurons. Apo E4 and all the Apo genes are not seen as a causative factor or regulator of Alzheimer’s Disease progression, they just confer a higher risk of developing Alzheimer’s Disease (MDConsult, 2000, Fine, 1999, Mayeux, 1998, Rebeck, 1997).
See Figure
There are mutations that can cause Alzheimer’s Disease also. Mutations in the presenilin genes are seen mainly in early onset Alzheimer’s. The gene for presenilin-1 (PS-1), is found on chromosome 14 and is present in 40% of early onset Alzheimer’s Disease patients. The gene for presenilin-2 (PS-2) is found on chromosome 1 and has a low mutation rate. However, combined PS-1 and PS-2 mutations are found in 75% of the familial early onset Alzheimer’s Disease patients (Fine, 1999). The presenilin proteins coded for by these genes are incorporated into the endoplasmic reticulum membrane (Drouet, et. al., 2000, Fine, 1999). What is the effect of these presenilin proteins? They cleave the APP protein leading to beta-amyloid peptide formation and eventual plaque formation as discussed in the beta-amyloid section. PS-1 and PS-2 cleave the APP to beta-amyloid segments 40 and 42 amino acid residues long. In Alzheimer’s Disease, the 42 amino acid long beta-amyloid is seen more often than the 40 amino acid long, although the exact consequences are unknown. Mutations in PS-1 and PS-2 lead to higher 42 amino acid length beta-amyloid (Fine, 1999). Another possible affect of mutated presenilin proteins is to destabilize calcium homeostasis within the cell, possibly through interaction with calcium binding protein, although this link is not definite (Drouet, et. al., 2000).
There may also be mutations in the Amyloid Precursor Protein (APP) discussed previously. The gene for this protein is found on chromosome 21. There can be a missense mutation of the 717 amino acid residue of APP leading to early onset Alzheimer’s Disease (Fine, 1999). One of the interesting points of the APP gene being on chromosome 21 is that trisomy of chromosome 21 is the main cause of Down’s Syndrome. Down’s Syndrome patients invariably develop early onset Alzheimer’s Disease. No firm link has been established here though between chromosome 21 causing Alzheimer’s Disease in non-Down’s Syndrome patients.
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www.alzforum.org Excellent site with information for patients and caregivers, clinicians, and the cutting edge of scientific research into Alzheimer’s Disease
www.mdconsult.com Excellent source for information for patients and clinicians on some research and treatment for those with Alzheimer’s Disease
summary | neurofibrillary tangles-the tau protein | inflammatory response | beta amyloid plaques
