Alzheimer's Disease

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(No Transcript)
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Neurodegenerative Disorders

• Huntingtons disease
• Parkinsons disease
• Amylotrophic lateral sclerosis
• Alzheimers Disease

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Some Facts

• Degenerative brain disorder developed in
  adulthood (brain cells die)
• Progressive and irreversible decline in memory
  and other cognitive abilities
• 4.5 million people in America

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Symptoms

• Forgetfulness and loss of smell
• Memory loss becomes more severe
• Language, perceptual, and motor skills
  deteriorate
• Mood becomes unstable
• Lost of mobility and control of body functions
• Death

http//www.alzheimers.org/rmedia/mediaroom.htmani
mation
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Diagnosis

• Diagnosis by exclusion
• Medical history and mental status exams
• Physical examination
• Neurological exam
• Blood count
• CT, PET, and MRI scans to detect brain volume and
  activity
• Confirmed by autopsy
• Tau and ß-amyloid test?
• Other developed tests have been unsuccessful

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Risk Factors

• Genetics
• Apolipoprotein E4 (APOE4)
• Deletions in gene coding for a-macroglobulin
  (serum protease inhibitor)
• LDL gene?
• Type II Diabetes
• Down Syndrome
• High cholesterol levels
• Stroke and previous head injuries
• Tobacco
• High homocysteine concentration in blood

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Types

• Familial Alzheimers Disease
• Caused by a genetic mutation
• All are early onset (younger than 60 years)
• Accounts for 10 of the cases
• Sporadic Alzheimers Disease
• Most common (90 of the cases)
• Typically occurs after age 65

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Familial Autosomal AD

• Older patients of Downs syndrome also have
  neurofirillary tangles and senile plaques

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Martin, Joseph, N Engl J Med
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Hypotheses

• Amyloid hypothesis
• ß-amyloid protein
• tau hypothesis
• tau protein

http//www.alzheimers.org/rmedia/mediaroom.htmani
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Senile Plaques

• Appear first in the cerebral cortex
• Results from improper cleavage of APP
• Made by ß-amyloid, tau, ubiquitin,
  a-antichymotrypsin, apolipoprotein E, presenilins
  1 and 2, a-macroglobulin
• ß-amyloid fragment (39 43 a.a.) is sticky and
  aggregates
• Forms intracellularly and transported outside of
  the neuron

http//www.pubmedcentral.nih.gov/articlerender.fcg
i?toolpubmedpubmedid12525689
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Senile Plaques

• Activates de immune system
• Disrupts neuron communication and inflammation
• ß-amyloid facilitates Ca2 entry to neurons
• Mitogen-Activated Protein Kinase (MAPK)
• Inhibits ubiquitin degradation
• Insufficient to cause cell death
• High metal concentration

APP Copper binding domain
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Senile Plaques
http//www.alzheimers.org/rmedia/mediaroom.htmani
mation
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Senile Plaques
http//www.alzheimers.org/rmedia/mediaroom.htmani
mation
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Senile Plaques
http//www.alzheimers.org/rmedia/mediaroom.htmani
mation
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Senile Plaques
known mutations
Martin, Joseph, N Engl J Med
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Amyloid Tracer

• Compound B highlights ß-amyloid
• Currently under human trials
• Developed at the University of Pittsburgh
  Sweden's Uppsala University

University of Pittsburgh Medical Center
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PIB
Proc Natl Acad Sci U S A. 2003 October
14 100(21) 1246212467.
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Presenilin
Presenilin 1 mutations
Presenilin 2 mutations
Martin, Joseph, N Engl J Med
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Astrocytes and Microglia Cells

• Astrocytes become more numerous and produce
  prostaglandin mediated inflammation
• Microglial cells produce free radicals
• Produce InterLeukin-1ß (IL-1ß) and Tumor
  Necrosis-a (TNF-a) (inflammatory cytokines)
• Induce enzymes like nitric oxide synthetase
• Inflammation damages neurons causing neuron death

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Neurofibrillary Tangles

• Typically begin in the entorhinal cortex
• Visualized as paired helical filaments on
  electron microscopy
• tau protein maintains the structural integrity of
  microtubules within neurons
• In AD, tau protein becomes hyperphosporylated
• Hyperphosporylated tau binds to each other
  forming NFTs
• Neurons full of NFTs die

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Neurofibrillary Tangles
http//www.alzheimers.org/rmedia/mediaroom.htmani
mation
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Neurofibrillary Tangles

• NFTs not present in all cases
• NFTs kill output neurons mostly
• Cholinergic neurons (Ach)
• Large pyramidal neurons
• Output neurons in the hippocampus

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Apolipoprotein

• Protein portion of lipoproteins (LDL, HDL, etc.)
  that transport cholesterol
• Synthesized in the liver, by the brain
  astrocytes, and oligodendrocytes
• Does not cross the Blood Brain Barrier
• Important risk factor

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Apolipoprotein E

• 299aa glycoprotein
• Acts as the binding site for LDL receptors
• Allows lipids to get into the cell
• Major lipoprotein for lipid transport between
  neurons
• cholesterol used for synapse plasticity and
  repair of damaged neurons
• Removes oxidized lipids from the brain
• Three common forms (E2, E3, and E4)
• Usually secreted after brain damage

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Insulin

• High insulin concentration stimulates nitric
  oxide synthetase
• Combines nitric oxide with superoxide to produce
  peroxynitrite
• Peroxynitrite causes Tyr nitration
• AD patients show high Tyr nitration in both
  neurons and glial cells

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Tobacco

• Nicotine in rats produces elevation of Nerve
  Growth Factor, enhancing Acetylcholine production
  and release
• Nicotine reduces ß-amyloid production
• Incidence of AD is more than double for smokers
  compared to non-smokers

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Treatments

• Acetylcholinesterase inhibitors
• NMDA Receptor Antagonists
• Memantine (Namenda)
• ß-secretase (BACE) inhibitor?
• Anti-amyloid vaccine?
• Detoxification of ß-amyloid?
• Metal ions reduction (Clioquinol)?
• Vitamin E intake

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Cholinergic Neurons

• Regulate attention, the first stage of learning,
  and memory
• Use acetylcholine as a neurotransmitter
• Have more microtubules than other neurons

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Acetylcholinesterase

• Breaks acetylcholine
• Promotes aggregation of ß-amyloid

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AchE Inhibitors
Donepezil (Aricept)
Tacrine (Cognex)
Rivastigmine (Exelon)
Acetylcholine
Galantamine (Reminyl)
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NMDA Receptor Antagonist

• Memantine/Auxura/Namenda
• Regulates Calcium influx
• Replaces Magnesium Ions

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Clioquinol

• Chelates copper and zinc in vitro
• Treatment reversed the deposition of amyloid in
  the brains of mice with AD
• Clioquinol cut amyloid deposits in half over a
  nine week period with no adverse effects.