Jessica Schindler NBSN2006-001 Fall2015
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.
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
Role of the Nurse
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.
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,