ALZHEIMER’S DISEASE

PRESENTED BY:SEC C1-GRP. 7

INTRODUCTION

Alzheimer’s disease is a generally a sporadic incurable neuropsychiatric condition in which progressive impairment of cognitive function occurs and frequently accompanied by affective and behavioral disturbances. Two forms familial and sporadic.

OBJECTIVESAt the end of the discussion, the students should be able to:

1.Define and characterize Alzheimer disease2. Know its etiology and risk factors for its development3. Determine the structural and biochemical changes resulting to this disease.4. Discuss the molecular mechanism and hypotheses in the formation of AP and NFT5. Differentiate AP from NFT6. Describe the imbalances of hormones/NTA involved in this particular disease.7. Give possible association of the following with AD: LP, cholesterol, inflammation and immune response, metal toxicity and free radicals and cigarette smoking8.Enumerate some preventive and treatment management for AD and the rationale behind the use of different drugs.

DEFINITION OF TERMS

1. Amyloid Protein Precursor- a trasmembrane protein precursor

2. Apolipoprotein- a lipoprotein which plays a role in the movement and distribution of cholesterol in repairing nerve cells during development and after injury.

3. Tau protein- tubule-associated protein

ETIOLOGY

- Generally of an unknown etiology- Researchers are finding specific biologic factors involved with Alzheimer’s disease. Various environmental and genetic players of appear to contribute to or trigger the process by which these factors destroy nerve cells leading to this disease.

RISK FACTORS

-Age-Gender-Family History-Heart and Vascular Disease-Lifestyle

GENETIC DETERMINANTS OF AD

Late OnsetApolipoprotein E4(ApoE4) coded from the mutation of

chromosome 19 - causes a weak a loose bonding to tau proteins. - causing tau to freely interact with another molecule of

tau. - formation of paired-helical filaments (precursor of NFT) “Increase level of ApoE4, Increase risk of Alzheimer’s

Disease”

GENETIC DETERMINANTS OF AD

Early OnsetAPP coded from chromosome 21 Possible normal function- May stimulate cell division and adhesion;

possible role in signaling.- May also function as nerve protector.- Overproduction of APP in Down Syndrome

GENETIC DETERMINANTS OF AD

Early Onset- Presenilin 1 coded from chromosome 14- Presenilin 2 coded from chromosome 1 - integral proteins - components of proteolytic complex involve in APP processing and

degradation.

Possible normal function are: - membrane and protein trafficking, signaling and apoptosis.

Defective genes: - accelerates Aβ plaque formation.

Biochemical Changes

Beta Amyloid (Aβ)

Tau Proteins

Amyloid Precursor Protein (APP)

• An integral membrane protein• Concentrated in the synapses of neurons• Its primary function is not known, though it has been

implicated as a regulator of synapse formation, neural plasticity and iron export

• Cleaved by enzymes: α,β,ϒ secretase

- Residues: Aβ42- Toxic amyloidogenic Aβ40- Nontoxic P3- Nontoxic

Beta Amyloid (Aβ)• A peptide of 39 – 42 Amino acids• Derived from transmembrane APP• Accumulation of Aβ fibrils leads to formation

of senile plaques in AD

Asp – Ala – Glu – Phe – Arg – His – Asp – Ser – Gly – Tyr – Glu – Val – His – His – Glu – Lys – Leu – Val – Phe – Phe – Ala – Glu – Asp – Val – Gly – Ser – Asp – Lys – Gly – Ala – Ile – Ile – Gly – Leu – Met – Val – Gly – Gly – Val – Val – Ile - Ala

Tau Protein

• are proteins that stabilize microtubules.• Normally phosphorylated• Increase Influx of Ca++ causes

hyperphosphorylation • Hyperphosphorylation of the tau protein can

result in the self-assembly of tangles of paired helical filaments and straight filaments

Alzheimer’s Disease

Tau HypothesisAβ HypothesisCholinergic

Hypothesis

Tau Hypothesis

Hyperphosphorylation of tau

Detachment of Tau from Microtubules

Increase free tau protein

Aggregation of tau proteins

Neurofibrillary Tangles

Beta Amyloid HypothesisAbnormal Cleaving of APP

Formation of Beta Amyloid

Misfolding of Aβ

Aggregation of Aβ

Amyloid Plaque

Cholinergic Hypothesis

• The oldest hypothesis for AD causation.• Cholinergic hypothesis holds that a reduction in

neurotransmitter Acetylcholine is responsible for AD.Proposed mechanism• Evidence shows neocortical cholergic function declines

rapidly in the early stages of AD.• Decreased Acetylcholine is proposed to alter the normal

neuron signal transduction pathway, resulting in observable histopathological changes:– Hyperphosphorylated Tau, causing neurofibrillary tangles– Cleaving of APP into β-Amyloid plaques

Hormonal Imbalance and Neurotransmitter

Lack of Estrogen in aging women increases the risk for A.D

Estrogen primarily blocks production of Aβ. It also offers anti oxidant protection, and regulates glucose levels in the brain

Acetylcholine – decreased Ach levels in AD is the primary reason in the cholinergic Hypothesis

Possible Association with AD

A. Lipoproteins and CholesterolB. Inflammation and immune responseC. Metal ToxicityD. Free RadicalsE. Cigarette/Tobacco Smoking

TREATMENT

NO CURE

Symptoms Cholinesterase Drug Inhibitors- Aricept (donezepil HCL)- Exelon(rivastigmine) - Razadyne (galantamine)

PREVENTION

- Administration of NSAIDS- Calcium Channel Blocker- Statins- Dietary Intake

References• Lippincott’s Illustrated Reviews on Biochemistry (4th Edition)• Harper’s Illustrated Biochemistry (28th edition), (25th edition)• Harrison’s Principles of Internal Medicine (15th edition)• Will’s Biochemical Basis of Medication• Online Sources:

http://www.ebi.ac.uk/interpro/potm/2006_7/Page2.htm

http://alzheimers-review.blogspot.com/2011/01/therapeutic-effect-of-cigarettes.html

http://www.nia.nih.gov/Alzheimers/Publications/Unraveling/Part2/hallmarks.htm

http://www.helmedica.gr/items-6-7-en.htm

http://adam.about.net/reports/000002_3.htm

http://www.cellsignal.com/reference/pathway/alzheimers_disease.html

http://www.wisegeek.com/what-are-amyloid-plaques.htm

http://www.youtube.com/watch?v=NjgBnx1jVIU&feature=related