Alzheimer’s disease (AD)
In fact, the pathology of Aβ and tau in AD is not fully elucidated, it has been implied that intracellular Aβ oligomers impaired the proteasome activity which is contributing to the age-related pathological accumulation of Aβ and tau in AD mice model when Aβ oligomer levels are high (Tseng et al., 2008). Together with Aβ, tau which is an intrinsically unstructured protein associated with microtubules also involves in the pathology of AD (Lee et al., 2013; Selkoe, 2011). Whether the significance of Ub-independent and Ub-dependent degradation of tau within the cell through the UPS and autophagy is contradictory, accumulation of ubiquitin positive tau tangle, association of tau with diverse proteasome subunits and identifications of poly-ubiquitylated tau in different K-linkages (K6-, K11-, K48- and K63-linkages) have been suggested to the association of the cellular degradation machineries in AD (Lee et al., 2013). In parallel role of autophagy as a second line of the UPS also has been suggested that soluble tau is degraded via the UPS, whereas oligomeric tau aggregates are efficiently degraded through the autophagy-lysosomal system (Kruger et al., 2012; Lee et al., 2013; Wang and Mandelkow, 2012).
Post-modification of tau also influences the formation of tau aggregates. Acetylation of tau by histone acetyl-transferase p300 prevents degradation of phosphorylated tau and reversely, deficiency of deacetylase SIRT1 enhanced levels of acetylated-tau aggregation (Cohen et al., 2011; Min et al., 2010). Furthermore, the identification of Hsp90-CHIP complex selectively degrades phosphorylated tau propose the active role of the UPS on elimination of the aberrant tau protein (Dickey et al., 2007; Salminen et al....
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..., 2007; Lowe et al., 1990). In another hand, overexpression of UCHL1 substantially restored the abilities of learning and memory in AD mouse (Gong and Leznik, 2007). In addition, a modern molecular genetic analysis discovers the novel familial recessive loss of function of UCHL1 leads to early-onset progressive neurodegeneration and this missense mutation within the ubiquitin binding domain of UCHL1 (E7A) dramatically compromises ubiquitin binding and hydrolase activity compared to the previous mutation in UHCL1 (I93M) in vitro (Bilguvar et al., 2013). Apparently, mutations of ubiquitin-related proteins (PAKIN and UCHL1) and disturbance of proteasome, mainly loss of functions in the UPS manifest that the collapsing of proteostasis by the consequence of the failure in elimination of aberrant proteins, not all but mostly exacerbates to the pathology of many diseases.
The Alzheimer’s Association (2005) defines the disease as “a progressive brain disorder that gradually destroys a person’s memory and ability to learn, reason, make judgments, communicate, and carry out daily activities”. Contrary to popular belief, Alzheimer’s is not the result of normal aging, although it normally occurs more frequently in people who are over the age of 65 (Gruetzner, 1988). Studies performed on the brains of deceased Alzheimer’s patients show several irregularities. The most obvious abnormality is in the signal-transmitting chemicals, where a 40-90% decrease in the enzyme CAT is found. This enzyme lies in the cerebral cortex and hippocampus regions of the brain. When CAT is decreased, it causes cholinergic or acetylcholine-releasing nerve terminals to diminish. These chemicals are important for communication between nerves. Also found during these autopsies were double strands of neurofibullary tangles, senile plaque (decayed neural material), and granulovacular degeneration-all which are associated with mental impairment. Neurofibullary tangles normally do increase with age, but Alzheimer’s patients show a very high density of the tangles. The brain has also been found to contain abnormally high concentrations of aluminum (Weiner, 1987).
Although numerous stress conditions lead to an imbalance of proteostasis, aging is the most deleterious risk factor for the onset of protein aggregation diseases. The declined activity or inefficient assembly of the proteasome in aging process exacerbate collapsing of proteostasis further.
Zilka, N., Stozicka, Z., Kovac, A., Pilipcinec, E., Bugos, O., and Novak, M. (2009). Human misfolded truncated tau protein promotes activation of microglia and leukocyte infiltration in the transgenic rat model of tauopathy. Journal of neuroimmunology 209, 16-25.
Alzheimer’s disease or AD is an incurable disorder of the brain that results in loss of normal brain structure and function. In an AD brain, normal brain tissue is slowly replaced by structures called plaques and neurofibrillary tangles. The plaques represent a naturally occurring sticky protein called beta amyloid and in an Alzheimer’s brain, sufferer’s tend to accumulate too much of this protein. Neurofibrillary tangles represent collapsed tau proteins which, in a normal brain along with microtubules, form a skeleton that maintains the shape of the nerve cells. In Alzheimer’s disease, the tau proteins break loose from their normal location and form tangles. Without the support of these molecules, nerve cells collapse and die. As normal brain structure is lost with progression of the disease, brain function also degenerates. Patients afflicted with Alzheimer’s disease display a gradual mental decline. Initially, and most apparently, there is a loss of short-term memory. Eventually, as a patient progresses to later stages of the disease, the brain becomes so damaged that patients can no longer communicate or recognize immediate family or even themselves. They have difficulty walking and standing and frequently fall. In the final stages, they lose bladder and bowel control and have difficulty with swallowing, frequently leaving them malnourished and dehydrated. Eventually, they are forced to remain bedridden and, without the help of life-prolonging measures provided in a hospital, die. However, this level of deterioration is severe and may take as long as twenty years. Because of the disease’s slow progress and its usual later start in a person’s life, a victim of AD will usually die first of natural causes. Under the objectives ...
Clinically, Alzheimer’s disease is characterized by the accumulation of beta-amyloid plaque between living neurons in the brain (Sabbagh, 2008). This results in an excessive calcium influx inside the neurons and the breakdown of a protein called tau. Normally, the rol...
Alzheimer’s disease is a complex illness that affects the brain tissue directly and undergoes gradual memory and behavioral changes which makes it difficult to diagnose. It is known to be the most common form of dementia and is irreversible. Over four million older Americans have Alzheimer’s, and that number is expected to triple in the next twenty years as more people live into their eighties and nineties. (Johnson, 1989). There is still no cure for Alzheimer’s but throughout the past few years a lot of progress has been made.
There are three different abnormalities that can make up Alzheimer’s disease. The first abnormality is beta-amyloid peptide cut from APP, a membrane precursor protein (Marieb and Hoehn 2013). Too much beta-amyloid is toxic and causes plaque buildup between neurons that reduces levels of acetylcholine which makes is difficult to retrieve old memories and make new ones (Marieb and Hoehn 2013). Another abnormality of Alzheimer’s disease is the presence of neurofibrillary tangles inside the neuron. These tangles consist of tau, a protein that leaves its stabilizing role and binds to another tau molecule forming a neurofibrillary tangle. (Marieb and Hoehn 2013). Neurofibrillary tangles then kill the neuron. The final abnormality of Alzheimer’s disease is brain shrinkage. The brain shrink...
Aging affects all living organisms, which is characterized by the loss of cellular homeostasis causing systemic cellular dysfunction. In fact, both the mitochondrion and the actin cytoskeleton show age-associated declines in functions. As an organism age, mitochondria accumulate mtDNA mutations, which result in mitochondrial dysfunction. The actin cytoskeleton also declines with age. This affects establishment and maintenance of cell polarity as well as cellular and intracellular movement, which in turn contributes to age-associated declines in systems including the immune system and skeletal muscle. In addition, many age-related pathologies like neurodegenerative diseases, such as Alzheimer’s, display dysfunction in mitochondria and actin. Interestingly, Dr. Liza Pon’s
The Nervous System is one of the most important and complex system in the human body, because it works as the main control center. It regulates the sensory, integrative and motor function of the body. Everything we do, feel or think is directly linked to the Nervous System. An error in any of these functions could bring negatives consequences such as degenerative diseases later in life.
formed from hyperphosphorylation of tau protein. Since the tau protein is abnormal in AD, the
As the human brain ages, it reaches a stage where it starts to loses its abilities, primarily in the prefrontal cortex. A major risk factor is memory loss, caused by the hippocampus weakening with age. The hippocampus is involved with short and long term memory and is proven that in a human's early 20’s, neural connections begin to die off. As a result there are numerous defects that can develop in the human brain from aging. For example Alzheimer’s, strokes, parkinson's and dementia, are classified as neon green to represent toxicity within the brain. Blue is used to highlight the components used in the process of Alzheimer's. This occurs when there are too many proteins called “TAU” tangle and plaque blocks neural connections. Protective
A common finding is that amyloid, an insoluble fibrous cellular substance, is not processed correctly and a build up occurs. In individuals with AD, a higher amount of amyloid plaque is found in the brain than for someone following a normal aging process. An inflammatory response is activated which damages the nervous system. The plaque formation causes a chemical disruption that is believed to weaken the proteins that hold together microtubules, the organizational structures of neural cells. This disruption produces neurofibrillary tangles, leading to reduced cell division and neurotransmitter transport. A decrease of neurotransmitters is a trait common in patients with AD as many are important for memory development.2,
“Several transgenic mouse models of AD have been generated that exhibit age-related accumulation of Aβ without or with Tau pathology, and associated learning and memory deficits.” Mice with Aβ and Tau pathology that were subjected to intermittent fastening; results indicated that it can protect neurons against dysfunction. Other experiment results involving the “administration of alternate day fasting several months prior to Kaini acid suministration, the animal was more resistant to the degeneration; and learning and memory deficits where improved.” This type of fasting no only made the diseased animal resistant; but also improved it’s
Because A"β" is critical to the pathogenesis of Alzheimer’s disease, “it is imperative to understand the molecular and cellular basis of its production” (Bali 2010). The A"β" peptides themselves are formed from an Amyloid Precursor Protein, “ by the sequential action of of "β" - sycretase and "γ " secretase” and are released, forming plaques. The toxic properties of these plaques include the phosphorylation of tau, thus the creation of tangles in the brain, and neurodegeneration (Bali 2010).
Alzheimer’s Disease is named after a German doctor, who specializes in the brain and nervous system, named Alois Alzheimer. This Disease forms in the brain. Alzheimer’s is the most common form of Dementia, a general term for memory loss and other intellectual abilities serious enough to enter. The Tau protein ensures the tubes in your brain stay straight allowing molecules to pass through freely. In Alzheimer’s Disease the protein collapses into strands or tangles, making the tubes disintegrate. There is visible differences of brain tissue in the from misfolded proteins called plaques and tangles. Beta-Amyloid clumps block signals and communication between cells in the brain. Researchers agree that Alzheimer’s Disease is m...