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BY: SUZANNE DE LA MONTE, M.D. & JACK WARDS, M.D. PRESENTED BY: CAITLAN BLYDENBURGH Alzheimer's Disease is Type 3 Diabetes- Evidence Reviewed

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Introduction 5.4 million Americans are living with Alzheimer's disease. 25.8 million children and adults in the United States8.3% of the populationhave diabetes.

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Introduction Alzheimer's disease is a progressive neurologic disease of the brain which leads to the irreversible loss of neurons and the loss of intellectual abilities, including memory and reasoning

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Introduction Diabetes, describes a group of metabolic diseases in which the person has high blood glucose (blood sugar), either because insulin production is inadequate, or because the body's cells do not respond properly to insulin, or both.

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What is insulin? Insulin is a hormone that is produced by the beta cells Beta Cells- are cells that are scattered throughout the pancreas. The insulin produced is released into the blood stream and travels throughout the body. Insulin is an important hormone that has many jobs within the body. Most of the actions of insulin are directed at metabolism of carbohydrates, lipids, and proteins.

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What is insulin resistance? Insulin resistance is a condition where the cells of the body become resistant to the effects of insulin that is, the normal response to a given amount of insulin is reduced. As a result, higher levels of insulin are needed in order for insulin to have its effects.

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Introduction Alzheimer's is being called a neuroendocrine disease because it involves insulin resistance in the brain.

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Insulin In the Brain Why is insulin needed in the Brain? Like other cells in the body, neurons in the brain need glucose to fuel their activities.

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Insulin in the Brain In the brain, insulin has a number of roles to play. It promotes glucose uptake in the neurons of the hippocampal formation and the frontal lobes, areas that are involved in memory. It strengthens the synaptic connections between brain cells, helping to form new memories. It regulates the neurotransmitter acetylcholine, which plays an important role in learning and memory.

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Synapse http://science.cabot.ac.uk/?p=1427

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Review of Literature de la Monte SM, Wands JR. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer's disease. J Alzheimers Dis. 2005;7(1):4561. There are biochemical, molecular, and cellular abnormalities that come with AD neurodegeneration. These abnormalities include increased activation of signaling pathways, impaired energy metabolism, mitochondrial dysfunction, chronic oxidative stress, and DNA damage.

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Review of Literature Hoyer S. Causes and consequences of disturbances of cerebral glucose metabolism in sporadic Alzheimer disease: therapeutic implications. Adv Exp Med Biol. 2004;541:135152. Under scientific evaluation researchers have found that impairments in cerebral glucose consumption, and energy metabolism represent early abnormalities that occur before or during the initial stages in AD.

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Review of Literature Virkamki A, Ueki K, Kahn CR. Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J Clin Invest. 1999;103(7):931943. This led researchers to the concept that impaired insulin signaling plays a important role in the pathogenesis of AD. All of the correlations drawn can help to show that AD represents type 3 diabetes.

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Hypothesis If Alzheimer's Disease represents a form of diabetes mellitus then it may cause selective abnormalities in the brain, and there for can be referred to as type 3 diabetes.

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Methods and Materials Researchers utilized experimental models to demonstrate that diabetes mellitus- type molecular and biochemical abnormalities could be produced in CNS neurons and the brain through exposure to Streptozotocin (STZ). Streptozotocin (STZ) is a drug that causes diabetes because it is taken up by insulin- producing cells.

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Methods and Materials Mice were treated with a single intracerebral (ic) injection of STZ, and were allowed to grow older for 4 weeks. The mice were then subjected to Morris water maze tests of spatial learning and memory, and their brains were examined for biochemical, and molecular indices of AD- type neurodegeneration.

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Methods and Materials After the 4 weeks, from the time when the mice were given the STZ researchers found molecular, biochemical, and neuroanatomical pathologies that are associated with AD. This led researchers to test the hypotheses that AD- Type neurodegeneration could be reduced or prevented through early treatment with insulin- sensitizer antidiabetes agents such as peroxisome proliferator- activated receptor (PPAR) agonists.

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Methods and Materials Peroxisome proliferator-activated receptor agonists function at the level of the nucleus to activate insulin-responsive genes and signaling mechanisms. Its a drug used to help treat T2DM.

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Methods and Materials The experimental design involved treating rats with ic-STZ, followed by a single intraperitoneal injection of saline, PPAR-, PPAR-, or PPAR- activator. The doses used were considerably lower than those routinely given to treat T2DM. The planned major effects of the PPAR agonist treatments were to prevent brain atrophy, preserve insulin and IGF-2 receptors, prevent deficits in learning and memory.

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Methods and Materials Water Maze test to see if the drug worked. After the single intraperitoneal injection of saline, PPAR-, PPAR-, or PPAR- activator, the mice then retook the Morris

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Results The ic- STZ injected mice did not have elevated blood glucose or insulin levels But the brains showed striking evidence of neurodegeneration. They showed neuronal and oligodendroglia cell loss and cerebral atrophy. OLIGODENDROGLIA- ARE CELLS FOUND IN THE CENTRAL NERVOUS SYSTEM Loss of oligodendroglia could contribute to the early white matter degeneration and synaptic disconnection, which is shown in the early stages of AD.

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Results The compared results from the first Morris Water Maze test (after ic-STZ injection) and the second (after PPAR injection) test showed a significant improvement in learning and spatial memory tasks.

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Results

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Discussion The results from this study provided evidence that AD represents a form of diabetes mellitus that selectively afflicts the brain. The results of the Morris Water Maze tests, showed how the antidiabetes drug reduced typical characteristics of AD, which helped to show how AD mimics certain parts of Diabetes.

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Discussion The data provided strong evidence that AD is intrinsically a neuroendocrine disease caused by selective impairments in insulin and IGF signaling mechanisms, including deficiencies in local insulin and IGF production.

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Conclusion Therefore referring to AD as T3DM is justified, because the fundamental molecular and biochemical abnormalities overlap with T1DM and T2DM rather than mimic the effects of either one.

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Acknowledgements Ms. Gleason Older Science Research students Friends and family My Cousin Brooke

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Questions?