Alzheimer’s Disease and Myelin Degeneration

1. Alzheimer’s Disease and Myelin Degeneration RE|NOUS Jasmine Toor Week 6 Winter 2014 Meeting

2. Research paper • Bartzokis, George. Alzheimer’s Disease as homeostatic responses to age-related myelin breakdowns. Neurobiology of Aging vol. 32 (September 22,2009). • http://download.journals.elsevierhealth.com/pdfs/journals/0197-4580/PIIS0197458009002711.pdf

3. Overview • Traditional view of Alzheimer’s disease development vs. myelin model • Relationship between Myelin and Amyloid-Beta/Tau deposits • Future Research

4. Amyloid Hypothesis • Amyloid Hypothesis (AH) essentially is the idea that Alzheimer’s Disease occurs from the accumulation of amyloidbeta in the brain. • Some clinical trials have been able to reduce Aβ deposits in the brain but that did not have an effect on dementia in patients of those trials. • What does this mean?

5. Myelin Model • The myelin model of the human brain proposes that the processes of myelin development, maintenance, and its eventual breakdown are essential to understanding our unique cognitive and behavioral trajectories through life (Bartzokis, 1342). • The production, maintenance and repair of myelin sheaths and the susceptibility of all of these processes to genetic variants and environmental dangers is what puts our species at risk for neuropsychiatric disorders. • Myelin model considers brain circuits in their entirety and complements as well as integrates the lesion-based and genetic theories of Alzheimer’s disease into the model • Goal of paper is to look at APP and amyloidbeta in terms of myelin repair and maintenance

6. Myelin Degeneration Through Life

7. Myelin and Alzheimer’s Lesions • Myelin repair and maintenance uses the same processes ofthose that produce the common lesions seen in Alzheimer’s disease • The paper believes that the age-related need for better repair mechanisms of myelin along with the genetic variability in the ability to produce the necessary repairs is what causes the various lesions associated with neurodegenerative disorders

8. Alzheimer’s as a uniquely human disease • Two major lesions associated with Alzheimer’s disease would be Aβand tau protein • Tau protein is not seen in even our closest primate species • The extensive scope and quantity of myelination is what makes the human brain different from that of other species

9. Brain Cholesterol • Myelin contains up to 80% of the brain’s cholesterol • Cholesterol contributes to a variety of brain processes • The cholesterol is metabolically expensive to synthesize and therefore recycled from broken down myelin • The recycling of this myelin is depending on various proteins such as APoE • APoE and myelin are both severely degraded in old age and even more so in Alzheimer’s patients

10. Later life Oligodendrocytes • Compared to earlier- myelinatingoligodendrocytes later-myelinating cells support thinner and structurally more vulnerable myelin sheaths. • These later life cells produce sheaths that are more susceptible to myelin breakdown and neuronal degeneration

11. Iron • Higher brain iron levels have been consistently seen in Alzheimer’s patients as well as many other neurodegenerative diseases • 70% of the brain’s iron is housed in the myelin, and iron production only increases with age • Theory is that the iron is contributing to the toxicity and thus degeneration of the myelin

14. Future Research • Target therapies that increase myelin health, resilience, and repair efficiency • Management of age-related increases in iron as a means of treatment and prevention • Increasing APoE levels may be effective by promoting both efficient cholesterol recycling and removal of inflammation-promoting myelin debris that may help combat age-related reduction of successful remyelination