Alzheimer's Disease

Jessica Schindler NBSN2006-001 Fall2015

Introduction

This Newsletter is written to introduce new information on Genetics research with Alzheimer's Disease and to educate the public about the mechanisms of the disease while also exploring what might be the causative factors. The newsletter will focus more on late-onset Alzheimer's Disease which is more complex and multifactorial than early-onset. It is known to involve a combination of gene variants and environmental factors that contribute to an increased risk.

The Genetics of Alzheimer's Disease

The specific cause of Alzheimer disease is unknown. According to Internationale Stichting Alzheimer Onderzoek (2013) two types of lesions occur in the brain 10 to 15 years before symptoms appear called senile plaques and neurofibrillary tangles.


Senile plaques are composed of amyloid-beta protein. Amyloid protein-precursor (APP), a large protein on the surface of the neuron is normally cut off of the neuron by enzymes: α-secretase and γ-secretase (Porth, 2011). This frees a protein called amyloid-beta which is normally removed from the body. For some reason, Alzheimer’s patients have an unregulated, excess amount of amyloid-beta that assembles to make insoluble fibers creating senile plaques. The other lesion is called neurofibrillary tangles which is composed of tau protein.


Neurofibrillary tangles occur because tau protein becomes defective causing it to detach from the microtubule of the neuron. Microtubules are the internal skeleton of the neuron which guides nutrients and molecules to the end of the axon. When tau detaches from the neuron’s microtubule it falls apart causing the neuron to degenerate and lose its connection to other neurons. The tau protein combines to form filaments in the neuron. These filaments make neurofibrillary tangles, and the neuron dies. The two types of lesions develop in different parts of the brain and follow a different pattern of movement from each other (Internationale Stichting Alzheimer Onderzoek, 2013).


Neurofibrillary tangles first develop in the hippocampus, the center for memory and learning. They follow a centrifugal movement eventually causing atrophy of the brain. Progression of lesions corresponds with the progression of the symptoms which begin with memory problems, followed by language issues, loss of recognition, and finally an inability to perform activities of daily living. But senile plaques are first seen in the cortex and then move toward the hippocampus (Internationale Stichting Alzheimer Onderzoek, 2013).


Understanding what proteins and enzymes are involved allows researchers to locate what genes code for these proteins so that they can see if there are mutations or variants that cause a defective pathway in how the body works. New research is delving into what enzymes metabolize amyloid-beta and what genes are linked to this.

Mechanisms and secrets of Alzheimer's disease: exploring the brain
MicroRNA-33 Regulates Amyloid-Beta Metabolism

Jackwang Kim and his fellow researchers used the knowledge that microRNA-33 (miR-33) has been implicated in AD pathogenesis to conduct two experiments where they genetically deleted miR-33 in in mice and inhibited it pharmacologically in another.

The microrna-33 study

The Journal of Neuroscience published the report of a study that looks at how microRNA-33 regulates ApoE lipidation and amyloid-beta metabolism in the brain. Jackwang Kim and fellow researchers wanted to see what the physiological function of miR-33 was in the CNS and whether it has a pathological role in AD. According to Porth (2011) allele4 of the apolipiprotein E (ApoE) gene found on chromosome 19 increases the risk off Alzheimer's disease and lowers the age of onset. Kim explains that there have been studies on brain lipid metabolism but its regulation by microRNA's is unknown. The researchers first part of the study found that miR-33 regulates amyloid beta levels in neural cells by testing levels in vitro. Next, they used a mouse model that produces human amyloid beta in the brain called APP/PS1 mice to see if inhibiting miR-33 could decrease amyloid beta levels. They used 2' -flouro/methoxyethyl-modified and phosphorothioate-backbone-modified antisense miR-33 (anti-miR-33) to treat 2 month old APP/PS1 mice. ABCA1 protein levels increased and amyloid beta levels decreased significantly. This demonstrates that an endogenous regulator of ABCA1 and brain-specific miR-33 antagonist could be an effective strategy to lower amyloid beta levels. The researchers don't believe regulation in the periphery will regulate ABCA1 in the brain. ABCA1 is a major cholesterol transporter that transfers cellular cholesterol onto lipid poor apolipoproteins and regulates ApoE lipidation in the brain (Kim, Yoon, Horie, Burchett, Restivo, Rotllan et. al, 2014).

Role of the Nurse

When the nurse stays knowledgeable about new genetics research the nurse will be able to communicate their knowledge to the patient and other healthcare providers caring for the patient. If a nurse has read this study they will be able to tell a patient who is worried about getting Alzheimer's disease that they should not worry. There are drugs that slow its progression and research is continuing to make new strides in finding the cause and new treatments. The nurse can recommend that the patient look into a new treatment that the healthcare provider may not know about. Following genetic research allows the nurse to know when to recommend that a patient see a genetics counselor and have genetic testing done. The nurse role is all-encompassing. The nurse provides care to the patient and advocates for their best interest. The nurse collaborates with other healthcare providers to inform what is going on with the patient and to report changes in health status. Nurses take part in research ensuring the study follows ethical guidelines. The nurse educates and clarifies what the doctor explained. Nurses want to be leaders in the healthcare field and to be a leader one must stay up to date with current medical research and news to be able to utilize this information in their practice.
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Worthiness

Continuing to research about how the different proteins and enzymes work in our brain is very important to understanding how and why senile plaques and neurofibrillary tangles occur in the brain. It will unravel what the underlying factors are that cause Alzheimer's disease. As we better understand the disease the closer we will get to better medications and a cure.
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Impact on Future Medicine Practice

The microRNA-33 study is very important to future medicine practice. It has found a potential therapeutic strategy for Alzheimer's disease. Pharmacological inhibition of miR-33 via antisense oligonucleotide decreased amyloid beta levels in the cortex of APP/PS1 mice. This increased lipidation of brain ApoE and reduced amyloid beta by inducing ABCA1 (Kim et. al, 2014). Further research needs to be done to better understand how ApoE 4 gene is involved, and what other genes are involved. As we start to better understand how Alzheimer's develops we will become closer to inventing a drug that can cure the disease verses just slowing down the progression. One day doctors may even be able fix the gene that is involved with the disease.

Works Cited

Internationale Stichting Alzheimer Onderzoek, Alzheimer Forschung Initiative e.V., La Ligue Europeenne Contra la Maladie d’Alzheimer. (2013) Mechanisms and secrets of Alzheimer’s disease: exploring the brain. (Online video). Retrieved from: https://www.youtube.com/watch?v=dj3GGDuu15I&feature=youtu.be.


Kim, Jackwang. Yoon, Hyejin. Horie, Takahiro. Burchett. Restivo, Jessica. Rotllan, Noemi. Ramirez, Cristina. Verghese, Philip. Ihara, Masafumi. Hoe, Hyang-Sook. Esau, Christine. Fernandez-Hernando, Carlos. Holtzman, David. Cirrito, John. Ono, Koh. Kim, Jungsu. (2014) MicroRNA-33 Regulates ApoE Lipidation and Amyloid-Beta Metabolism in the Brain. Journal of Neuroscience. Retrieved from: http://www.jneurosci.org.proxy.libraries.uc.edu/content/35/44/14717.full


Porth, Carol Mattson. (2011) Essentials of Pathophysiology. Wolters Kluwer Health. Lippincott Williams & Wilkens,