1. Alzheimer’s- Disease of Death Corlisa Dixson Chem 4700-Protein Structure Dr. Kirberger Spring 2015

2. What is Alzheimer’s?  Alzheimer's is a type of dementia that causes problems with memory, thinking and behavior.  Alzheimer's is the most common form of dementia.  Alzheimer’s disease is driven by the production and deposition of the β- amyloid peptide (Aβ).  Dr. Alois Alzheimer.

3. Formation of Alzheimer’s  β-Amyloid Peptide (Aβ) is a 42-residue product resulting from two sequential cleavages of the amyloid precursor protein (APP)  Amyloid Precursor Protein (APP)- transmembrane protein with no clearly defined function.  Aβ molecules aggregate to form misfolded oligomers.  Misfolded oligomers induce other Aβ molecules to also misfolded.  Misfolded Aβ induce the protein tau to misfold.  An chain reaction occur, which turns into a prion infection.  The amyloid plaques builds up and are toxic to nerve cells.

4. β-Amyloid Peptide  Aβ binds strongly to copper(II) ions in the body through its three histidine's.  Copper/Aβ complex is a moderately strong oxidizing agent.  In the reduced form, the copper/Aβ complex can generate destructive species such as hydrogen peroxide, hydroxyl radicals, and other reactive oxygen compounds.  Aβ/Copper complexes - inherits an similarity for cell membranes from its parent because it generated from a transmembrane protein.  copper(I)/Aβ complex generate radicals near the highly unsaturated lipid bilayers that make up membranes in the brain, resulting in extensive membrane damage through lipid peroxidation.  Aβ aggregates can form membrane-penetrating holes that allow ions to pass into and out of brain cells unregulated, including across the protective blood-brain barrier. http://www.rsc.org/Publishing/Journals/cb/Volume/2009/9/Alzheimers_facts.asp

5. β-Amyloid Peptide  Aβ binds to numerous other proteins, all with damaging consequences.  binding to catalase causes the enzyme to lose its hydrogen peroxide clearing function.  interaction with apolipoprotein E accelerates the aggregation of Aβ itself into toxic species.  insulin receptors in nerve cells it causes reversible memory loss and diabetes symptoms.  interaction with nervous system protein tau results in nerve cell collapse.  Greek Motif

6. Tau Proteins  Tau proteins are proteins that perform the function of stabilizing microtubules.  Tau proteins are produced through alternative splicing of a single gene called microtubule- associated protein tau (MAPT).  The proteins were discovered in Marc Kirschner's laboratory at Princeton University in 1975.  Tau proteins are mainly active in the distal portions of axons where they stabilize microtubules as well as providing flexibility.  The proteins work together with a globular protein tubulin to stabilize microtubules and aid the assembly of tubulin in the microtubules.  Tau proteins achieve their control of microtubule stability through isoforms and phosphorylation.  Hyperphosphorylation of tau proteins can cause the helical and straight filaments to tangle (referred to as neurofibrillary tangles). These tangles contribute to the pathology of Alzheimer’s disease. http://flipper.diff.org/app/items/info/5017

7. Stages Of Alzheimer’s  Stage 1: No impairment (normal function)  The person does not experience any memory problems. An interview with a medical professional does not show any evidence of symptoms of dementia.  Stage 2: Very mild decline  The person may feel as if he or she is having memory lapses — forgetting familiar words or the location of everyday objects. But no symptoms of dementia can be detected during a medical examination or by friends, family or co-workers.  Stage 3: Mild decline  Trouble remembering names when introduced to new people  Having noticeably greater difficulty performing tasks in social or work settings Forgetting material that one has just read  Losing or misplacing a valuable object  Increasing trouble with planning or organizing

8. Stages Of Alzheimer’s  Stage 4: Moderate decline  Forgetfulness of recent events  Impaired ability to perform challenging mental arithmetic — for example, counting backward from 100 by 7s  Greater difficulty performing complex tasks, such as planning dinner for guests, paying bills or managing finances  Forgetfulness about one's own personal history  Becoming moody or withdrawn, especially in socially or mentally challenging situations  Stage 5: Moderately severe decline  Be unable to recall their own address or telephone number or the high school or college from which they graduated  Become confused about where they are or what day it is  Need help choosing proper clothing for the season or the occasion  Still remember significant details about themselves and their family  Still require no assistance with eating or using the toilet

9. Stages Of Alzheimer’s  Stage 6: Severe decline  Lose awareness of recent experiences as well as of their surroundings  Remember their own name but have difficulty with their personal history  Distinguish familiar and unfamiliar faces but have trouble remembering the name of a spouse or caregiver  Need help dressing properly (ie shoes on the wrong feet)  Experience major changes in sleep patterns  Need help handling details of toileting  Experience major personality and behavioral changes, including suspiciousness and delusions  Tend to wander or become lost  Stage 7: Very severe decline  individuals need help with much of their daily personal care.  They may also lose the ability to smile, to sit without support and to hold their heads up.  Muscles grow rigid.  Swallowing impaired.

11. Treatment  Three cholinesterase inhibitors are commonly prescribed:  Donepezil (Aricept) is approved to treat all stages of Alzheimer's.  Rivastigmine (Exelon) is approved to treat mild to moderate Alzheimer's.  Galantamine (Razadyne) is approved to treat mild to moderate Alzheimer's.  No Cure https://theamazingworldofpsychiatry.wordpress.com/2010/10/25/review-drug-class- review-on-alzheimers-drugs http://www.dailyfinance.com/2011/05/24/fda-urged-to-ban-dangerous-alzheimers-drug healthimpactnews.com

12. Work Cited Alz.org,. 'Publications | Alzheimer's Association'. N.p., 2015. Web. 18 Mar. 2015. Asaumi M, et al. 'Interaction Of N-Terminal Acetyltransferase With The Cytoplasmic Do... - Pubmed - NCBI'. Ncbi.nlm.nih.gov. N.p., 2015. Web. 18 Mar. 2015. Ciechanover, Aaron and Yong Tae Kwon. “Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies.” Experimental & Molecular Medicine (2015) 47. Web.17 March 2015. Hyman, T. Bradley, and Spires-Jones, L.Tara. “The intersection of amyloid beta and tau at synapses in Alzheimer's disease.” Neuron. 2014 May 21;82(4):756-71.PMIC.Web. 13 March 2015. Murphy, M. Paul, and Harry LeVine. “Alzheimer’s Disease and the Β-Amyloid Peptide.” Journal of Alzheimer’s disease: JAD 19.1 (2010): 311. PMC. Web. 17 Mar. 2015. Robertson, Sally. 'What Are Tau Proteins?'. News-Medical.net. N.p., 2010. Web. 18 Mar. 2015.