ALZHEIMER S DISEASE. Neuroscience Julius Kim

ALZHEIMER’S DISEASE Neuroscience 04.28.06 Julius Kim The Impact of AD Once considered a rare disorder, Alzheimer°Ø s disease is now seen as a majo...
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ALZHEIMER’S DISEASE

Neuroscience 04.28.06 Julius Kim

The Impact of AD

Once considered a rare disorder, Alzheimer°Ø s disease is now seen as a major public health problem that is seriously affecting millions of older Americans and their families.

What is AD? Azheimer°Ø s disease is an irreversible, progressive brain disease that slowly destroys memory and thinking skills.

Although the risk of developing AD increases with age °©in most people with AD, symptoms first appear after age 60 °© AD is not a part of normal aging. It is caused by a fatal disease that affects the brain.

What is AD? AD Statistics°¶ . ¶UAD is the most common cause of dementia among peopl e age 65 and older. ¶UScientists estimate that around 4.5 million people now ha ve AD. ¶UFor every 5-year age group beyond 65, the percentage o f people with AD doubles. ¶UBy 2050, 13.2 million older Americans are expected to h ave AD if the current numbers hold and no preventive tre atments become available.

What is AD? ¶UPathological hallmarks: β-amyloid (senile) plaques neurofibrillary tangles decreasing acetylcholine secretion synaptic loss widespread neuritic dystrophy ¶UPsychological symptoms: gradual loss of memory, orientation, judgment, and reasoning. behavior abnormalities changing personality

Inside the Human Brain • The brain has billions of neu rons, each with an axon and many dendrites. • To stay healthy, neurons mu st communicate with each ot her, carry out metabolism, a nd repair themselves. • AD disrupts all three of thes e essential jobs.

Inside the Human Brain

Microtubules are like railroad tracks that transport nutrition and other molecules. Tau-proteins act as “ties” that stabilize the structure of the microtubules. In AD, tau proteins become tangled, unstabilizing the structure of the microtubule.

Beta-amyloid Plaques Amyloid precursor protein (APP) is the precursor to amyloid plaque. 1. APP sticks through the neuron membrane. 2. Enzymes cut the APP into fragments of protein, including betaamyloid. 3. Beta-amyloid fragments come together in clumps to form plaques. In AD, many of these clumps form, disrupting the work of neurons. This affects the hippocampus and other areas of the cerebral cortex.

Risk factors

I. II. III. IV. V.

Mutated Amyloid precursor protein (APP) Mutated Presenilin 1 (PS1) Mutated Presenilin 2 (PS2) Apolipoprotein E4 (APO E4) Hyperphosphorylated Tau

Focusing on forming of Beta-amyloid Plaques

Mutation in APP and PS1,2 - APP gene : chromosome 21 9 mutations were identified - PS1gene : chromosome 14 84 mutation were identified - PS2 gene : chromosome 1 rarely mutated => PS1 and PS2 : missense mutation, gaining toxic functio n -> result in an increased production of beta-Amyloid

Presenilin ¶UDiscovery of Presenilin(PS) emerged directly from research on the genetic basis of Alzheimer°Ø s disease ¶Uare key mediators of Notch signaling

*Notch signaling participates in the development of multicellular organisms by maintaining the selfrenewa l potential of some tissues and inducing the differentiation of others

Schematic of the dimer model of PS at the core of the •„-secretase complex Four proteins: presenilin nicastrin Aph-1(anterior pharynx defective-1) Pen-2(presenilin enhancer-2)

Sites of PS-mediated intramembrane proteolysis wit hin the transmembrane domains of APP

Summary of some known presenilin-mediated pathway

APP processing and A•‚ accumulation

Possible A•‚ dependent mechanisms of neurotoxicit y

Treatment Strategies • One could attempt to partially inhibit proteases that gene rate A-beta from APP • One could attempt to prevent the oligomerization of A-be ta or enhance clearance from the cerebral cortex • Based on the observation that A-beta aggregation is, in p art, dependent on the metal ions zinc and copper. This s trategy reasons that chelation of these ions in vivo may p revent A-beta deposition

Other treatment in use ¶UEstrogen and ginkgo biloba: possibly due to anti-inflamm atory or circulatory properties ¶UAnti-inflammatory drugs: limit the production of amyloid ¶UVitamin E ¶UStatin drugs- (for high cholesterol), reduce Alzheimer°Ø s ri sk. ¶UFolate-lowers the amino acid homocysteine (that increas es Alzheimer°Ø s and heart disease risk). ¶UAmpalex- seems to help memory loss

Interesting hypothesis Type II diabetes and AD • Type 2 diabetes subjects as compared to the non-diabeti c control group have double the risk of AD. • The oral diabetic medications that stimulate pancreatic •‚ cells to release more insulin have been shown to elevate the incidence of AD among diabetes patients ->Insulin treatment (hyperinsulinaemia) causes even great er risk of AD among the subjects.

Relation: insulin degrading enzyme(IDE) • Insulin dergrading enzyme degrades insulin, amylin and amyloid •‚ peptide

if the insulin level increases in the brain, it would inhibit IDE to degrade A effectively, which could cause A•‚ neurotoxicit y, and then AD.

Reference ¶U Bales,K.R., Dodart,J.C., DeMattos, R.B., Holtzman,D.M., and Paul,S.M. 2002 Apolipoprotein E, A myloid, and Alzheimer Disease Molecular interventions 2 363-375 ¶U

Brunkan, A. L. and Goate, A. M. 2005 Presenilin function and c-secretase activity Journal of Neurochemistry 93, 7 69°© 792

¶U

Churcher, Ian., Beher, Dirk. 2005 g-Secretase as a Therapeutic Target for the Treatment of Alzheimer°Ø s Disease Current Pharmaceutical Design, 2005, 11, 3363-3382

¶U Fischer,David F.,Dijk, Renske.,Jacqueline A., Sluijs , Nair,Suresh M., Racchi, Marco., Levelt,Chris tiaan N., Leeuwen Fred W.,and Hol,Elly M. 2005 Activation of the Notch pathway in Down syndro me: cross-talk of Notch and APP FASEB J. 19, 1451°© 1458 ¶U Gandy,Sam.2005 The role of cerebral amyloid •‚ accumulation in common forms of Alzheimer dise ase The Journal of Clinical Investigation 115 1121-1129 ¶U Gassen, G., Annaert, W., 2003 Amyloid, Presenilins, and Alzheimer°Ø s Disease Neuroscientist 9 (2):117°© 126



Mcshea, Andrew., Zelasko, D.A., Gerst, J.L., Smith M.A. 1999 Signal transduction abnormalities i n Alzheimer’s disease : evidence of a pathogenic stimuli Brain research 815 237-242

¶U Poirier, Judes Apolipoprotein E and Alzheimer°Ø s Disease : A Role in Amyloid Catabolism ANNAL S NEW YORK ACADEMY OF SCIENCES 81-90 •

Sisodia, Sangram S. 2000 An accomplice for •„-secretase brought into focus Science magagine 28 9 2296-2297

¶U St George-Hyslop, Peter H. 2000 Molecular Genetics of Alzheimer°Ø s Disease BIOL PSYCHIATR Y 47:183°© 199 ¶U Qiu, W. Qiao., Folstein, Marshal F. 2006 Insulin, insulin-degrading enzyme and amyloid- peptide i n Alzheimer°Ø s disease: review and hypothesis Neurobiology of Aging 27 190°© 198