alzheimer’s disease ppt
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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
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