Misfolding Alzheimer's Disease

The disease stem cells could fix is called Alzheimer’s Disease (AD). The reason I chose this topic is because I have seen first hand how badly someone who suffers from Alzheimer’s Disease is affected in their daily lives. This disease completely takes over their lives and they turn into a completely different person who can hardly function. AD is very tough on the loved ones of the person suffering from it because that person, most of the time has no idea what is going on or who their loved ones are. The memories for people with AD is completely gone and even the simplest tasks such as remembering to use the bathroom becomes difficult. The way stem cells could be feasible is because stem cell-based therapies could potentially treat

Scientists believe that the combinations of genetics, environmental factors, and lifestyle play a huge part in Alzheimer’s disease. Scientists are learning that age-related changes may harm neurons. These changes include shrinking of the brain, and inflammation. In early-onset genetic mutation is usually the cause, and people thirty to sixty represent less than five percent of people with Alzheimer’s disease. In late-onset

All the neurons work together like a tiny community; different groups take in information, produce energy, assemble equipment, and dispose of waste. In order for this “community” to run smoothly, the cells need to be able to handle and store information, and most importantly, correspond with other cells. Alzheimer's inhibits these cells from performing like the community; when cells incapable of carrying out their jobs, they die and cause permanent impairment to the brain. The suspected “culprits” are tangles and plaques. Plaques are accumulations of a protein particle known as beta-amyloid; these deposits concentrate in the spaces between brain cells. Tangles are contorted fibers of a different protein called tau, that collect inside the nerve cells. Plaques and tangles cut off communication among cells, thus hindering the “community” and killing

The brains of AD patients display characteristic 'plaques' and 'neurofibrillary tangles', the proliferation and abnormal formation of these abnormal proteins is the basis of the processes which cause AD.  Apolipoproteins enhance the breakdown of beta amyloid in the brain.   APOE4 which was mentioned earlier as the main risk factor, is a variant of these proteins which is less effective at breaking down beta amyloid than the others in it's class.  This explains why individuals with one or two alleles for APOE4 have a notable build up of beta amyloid surrounding the neurons of the brain.  A substance called amyloid precursor protein (APP) is found penetrating the cell membranes of properly functioning neurons, which helps neurons grow, function, and repair damage that occurs.  Through interaction with an unknown enzyme, APP is broken down into shorter segments which form 'fibrils' of beta amyloid which clump together outside of the neurons and eventually progress to form the 'plaques' of AD. Excess beta amyloid is believed to alter the calcium homeostasis of neurons which is believed to induce increased apoptosis of neurons, leading to an overall loss of neurons over time.  Beta amyloid is also found to build up in, an inhibit proper function of the neuronal mitochondria, interfering with normal glucose metabolism which leads to neuron death and loss of brain volume (this is why brain imaging of these patients shows decreased glucose metabolism).  The beta amyloid is predominately thought of as an extracellular

PSEN1 and PSEN2 are polytopic membrane proteins (Davis et.al., 1998) that form the catalytic core in the protease γ-secretase (Francis et.al., 2002), which is responsible for the proteolysis of APP (Navivaeva & Turner, 2013). When there is a mutation at the loci for PSEN1 and PSEN2, located on chromosome 14 and 1 respectively, the activity of γ-secretase is altered resulting in changes in the proteolysis of APP and increased formation of Aβ (Qain et.al., 1998). Due to the increase of Aβ, amyloid plaques aggregate quickly causing early-onset of AD.

Many older people forget the name of close relatives or misplace things from one place to another. This type of forgetfulness is normal. But, forgetting how to reach home, getting troubled in places and person knows well, or asking questions continuously can be signs of a more serious problem. It is a disease of the brain that started slowly and gets worse as the time progresses. Alzheimer’s is a progressive destroying of brain tissue that primarily strikes people over the age of 65. Brain functions such as memory, comprehension, and speech deteriorate. The term first introduced by Dr. Alois Alzheimers in 1906. Memory is lost first. As days passes, attention tends to distracted, simple calculations become hard, and ordinary daily activities become difficult, accompanied by angry. These symptoms will worsen at night. Gradually mood changes occur like, outbursts of anger, fear to strangers, and deep apathy. There are mainly 3 factors that increase the likelihood of Alzheimer’s disease are brain changes, lifestyle and heart health, past head trauma.

At the beginning of this experiment, students believed in many misconceptions about Alzheimer’s and didn’t really understand the disease in full. When they took the pre lecture survey, the highest score was only a 9/14, with the average only being 43.17%. As, stated in the experimental design, the survey asked about the 7 stages of Alzheimer’s, the pathology and cost of the disease, and other facts and figures. The lesson plan mirrored the survey questions by addressing them through both a lecture and conversation based discussion. The students then played a game of Kahoot! and ideas that were heavily missed were reinforced. Overall the students found enjoyment in the lesson, and that it was very informative. Students then took part of a simulation

Amyloid precursor protein (APP) has many functions and regulations. This protein is involved in neural development. Many may know it for its involvement in the pathology of Alzheimer disease as well as other neurodegenerative diseases. However, APP is a developmental gene. This gene regulates neurons, their differentiation as well as migration. This gene is also involved in neurite outgrowth and the regulation of synaptic function (1). Despite knowledge of these functions, many functions of APP is still unclear (2).

The majority of APP undergoes non-amyloidogenic processing via consecutive clevage by α - and γ-secretases within the Aß domain resulting in nonpathogenic fragments, sAPPa and C-terminal fragments (CTFs, (Gong et al., 2010; Vetrivel & Thinakaran, 2006). APP also undergoes sequential proteolytic cleavage by β- and γ- secretases to generate Aβ peptides, as well as, sAPPβ and CTF. The role of Aβ leading to AD was first proposed by a study in the year 1984 (Glenner & Wong, 1984). The authors hypothesized that AD is a "cerebral amyloidosis", in which cerebral β-amyloid triggers dementia and the subsequent disease etiology. This central amyloidosis thesis was later reinterpreted and reported as the “amyloid cascade hypothesis” of AD. (Glenner & Wong, 1984; Hardy & Higgins, 1992; Tanzi & Bertram,

Studies have shown that the absence of PSEN1 gene has no effect on the cleaving process of alpha and beta secretase of the extracellular domain of APP. However, its absence does prevent the cleavage of the transmembrane domain of APP by gamma secretase. This further leads to the accumulation of carboxyl-terminal fragments of APP. Furthermore, the production of amyloid peptide drops by 5 folds. A mutation in the PSEN1 gene causes an inhibition of PSEN1 activity and is a potential target for anti-amyloidogenic therapy in Alzheimer's

As scientists, we are always trying to discover the answers to the how and why questions that comes up as science progresses. We all know that nothing is ever straight forward and sometimes we end up with more questions than answers from our obtained results but this is not always a negative. A major area of interest today is the development and progression of amyloid diseases such as Alzheimer’s’ disease, Huntington’s disease, and transmissible bovine spongiform encephalopathy. Despite extensive studies conducted on each one of these diseases, little is really known about their development and progression because little is known about the mechanism behind amyloid fibril formation – the common link found in all of these diseases. Over the

The central dogma of molecular biology conveys the idea that genetic information passes from DNA to RNA before ‘culminating in protein synthesis’ (Bandyra & Luisi, 2015). In essence, our genetic information is mainly used to code for specific proteins. There are 20 amino acids that can be bonded together in many different orders to form a number in excess of 10 million proteins across all biological organisms (Innovateus, 2015). Proteins have many different uses and functions, as well as modifications. Examples of these differences include glycoproteins with carbohydrates attached to be used in the cell membrane and phosphorylated serine molecules that act as metabolites. For the protein to be able to carry out its specific function, it must fold in the correct way. A precise path must be followed to allow the correct shape to be formed and if there is an error in this process, the misfolded protein could lead to dangerous diseases forming.

The primary structure of a protein is the sequence of amino acids. This creates a polypeptide chain because each amino acid acts as a monomer so when they bind together they form a polymer. When amino acids bond together, a peptide bond is formed. This occurs when there is a condensation reaction and H2O is lost from the two amino acids and a bond forms between the carbon on one amino acid and the

Protein misfolding diseases include highly debilitating degenerative disorders like Alzheimer’s and Parkinson’s diseases. The healthcare and financial burden linked to these pathologies has been steadily increasing over the past decade. Actually, there is currently no efficient treatment for misfolding diseases as well as no reliable early diagnostic techniques for them, in most cases. It is known that, in many cases, the cytotoxic effect of misfolded proteins is exerted through their self-assembly into amyloid-like protein aggregates. Unfortunately, the mechanisms responsible for the toxicity of protein aggregates are still not completely understood. The number of protein targets whose misfolding and aggregation is being shown to be associated with the onset of pathologic conditions is constantly increasing. Since the development of degenerative disorders is expected to increase at a similar rate than life expectancy, it is likely that in the years to come misfolding diseases would become more common and prevalent than previously thought. We should be prepared to deal with such a dramatic scenario and join research efforts to understand the molecular mechanism that underlie these devastating disorders without further delay.

The production of new proteins in the cell is fraught with danger arising from the dynamic and error prone protein folding pathways. In order to maintain proper cellular function, eukaryotes require rigorous quality control process to ensure correct production of proteins which can then be utilized by the organism. An essential form of quality control is the examination of newly-formed proteins to ensure correct folding.