Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Master of Science

Program

Physiology and Pharmacology

Supervisor

Cregan, Sean P.

Abstract

Alzheimer’s disease (AD) is partially characterized by excessive accumulation of amyloid-b (Ab) in the brain. Ab oligomers have greater toxicity than Ab fibrils and induce neuronal stress. The Integrated Stress Response (ISR) is activated in response to cellular stress and increases expression of activating transcription factor 4 (ATF4) and its target genes. Prolonged activation has been shown to induce aberrant cell death, and increased markers of the ISR have been found in the brains of AD patients. However, the exact mechanism of amyloid-b-induced death is largely unknown. We aimed to determine if Ab-induced neuronal death occurs through ATF4-mediated upregulation of its downstream pro-apoptotic gene PUMA. Primary cortical neurons were treated with Ab oligomers. Ab induced apoptosis in a PUMA-dependent manner in the presence of ATF4. These results suggest that therapeutics targeting ATF4 and PUMA may be successful in alleviating excessive neuronal death induced by amyloid-b in Alzheimer’s disease.

Summary for Lay Audience

Alzheimer’s disease (AD) is the most common type of dementia. AD is a degenerative disease affecting the brain. As the disease progresses, brain cells continually. One of the main proteins that is involved in the development of AD is amyloid-b. When levels of amyloid-bare elevated in the brain, the proteins tend to aggregate together. These clumps are harmful to brain cells, which are also called neurons. Amyloid-bcan cause high levels of stress in neurons. The Integrated Stress Response (ISR) is a pathway within cells that helps them to overcome a wide range of stress signals. When the ISR detects stress in the environment, it becomes activated and increases the expression of another protein called Activating Transcription Factor 4 (ATF4). ATF4 helps increase the production of proteins that can help the cell mediate the stress and return back to normal. However, sustained activation of the ISR has been shown to promote death signals within cells. High levels of many ISR proteins have been found in the brains of AD patients. The way in which amyloid-bcauses neuronal death remains largely unknown. We aimed to determine if amyloid-bcauses neuronal death through prolonged activation of ATF4 and increased expression of the pro-death protein PUMA. In the present study, neurons were treated with amyloid-baggregates. Amyloid-binduced neuronal death in the presence of both ATF4 and PUMA. When ATF4 or PUMA were removed from these neurons, amyloid-bdid not cause death. The results suggest that drugs targeting ATF4 and PUMA may be successful in reducing neuronal death caused by amyloid-bin Alzheimer’s disease.

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