Mechanisms of Alzheimers Disease Amyloid Precursor Protein APP

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Mechanisms of Alzheimers Disease Amyloid
Precursor Protein (APP)

• Ivan Millan

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What is Alzheimers

• Most common neurodegenerative disease
• Characterized by a difficulty in remembering
  names and recent events
• 6th most common cause of death in U.S. (as
  published by the CDC in 2008)
• Projected to see a dramatic increase with all the
  baby boomers reaching retirement
• CDC estimates 10 million baby boomers will
  develop Alzheimers
• Medical costs in the billions
• 91 billion in Medicare costs for 2005
• 36.5 billion in indirect costs (caregivers)
• 160 billion projected for 2010

(Alzheimers Association, 2008)
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Comparison of healthy brain and AD brain

• Alzheimers patients exhibit progressive loss of
  neurons
• Other physical symptoms include plaques and
  tangles

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Whats the mechanism behind Alzheimers?

• No known cause of AD
• Three genes implicated in early-onset
  Alzheimers
• Amyloid precursor protein (APP)
• Presenilin 1
• Presenilin 2
• APP gives rise to ß-amyloid which is found in
  plaques
• Leads to the idea that mutations in these genes
  causes Alzheimers
• Other models1
• Results from reduction of cholinergic synthesis
• Results from tau mutation, which leads to
  hyperphosphorylation

1(Van Broeck et al., 2007)
(Waring and Rosenberg, 2008)
5
(John H and Dennis JS, 2002)
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How does APP give rise to Beta Amyloid?

• APP is an integral membrane protein
• Trophic factor?
• Can be cleaved into smaller parts by secretases
  (the scissors in the picture)
• BACE is a ß-secretase that cleaves at the
  extracellular end
• PS1 is a ?-secretase that cleaves inside the
  membrane
• The product is Beta amyloid, which may be 38-43
  amino acids long

(Thinakaran and Koo, 2008)
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APP Binds DR6 and Causes Neuron Death

• Marc Tessier-Lavignes group recently found that
  amyloid precursor protein interacts with death
  receptor 6 and causes apoptosis of neurons in
  vivo and in vitro
• Uses caspase 6 instead of normal caspase 3
• Pathway is activated after neurotrophic
  deprivation

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APP Binds DR6 and Causes Neuron Death

• In vitro neurite outgrowth assay showing that
  anti-DR6.1 axons are are less susceptible to
  degeneration
• DR6 involved in degeneration of these axons
  (sensory axons).

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APP Binds DR6 and Causes Neuron Death

• Vibratome section of the superior colliculus
  showing increased axons (mice, P6)
• DR6 involved in degeneration of these axons.

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APP Binds DR6 and Causes Neuron Death

• In vitro, Caspase 6 is the main caspase involved
  in neuronal cell death.
• There are fewer degenerating neurons when caspase
  6 is knocked down

(Nikolaev et al., 2009)
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APP Binds DR6 and Causes Neuron Death

• APP protein shown in (h) with cleavage sites
• The pattern of DR6-AP binding in vitro is similar
  to the band when only N-APP antibody is used.
• C-terminus has a different band

(Nikolaev et al., 2009)
C-terminus
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APP Binds DR6 and Causes Neuron Death

• In vitro, NGF-deprived neurons that have the
  anti-N-APP polyclonal antibody exhibit fewer
  degenerating axons
• Very similar to anti-DR6.1 phenotype
• Supports idea that N-terminus of APP binds DR6

(Nikolaev et al., 2009)
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APP Binds DR6 and Causes Neuron Death

• After trophic factor deprivation, APP is cleaved
  by an unclear mechanisms to release the
  N-terminus region of APP
• This portion (about 300 residues) binds to DR6
  and activates the caspase cascade, resulting in
  degeneration

(Nikolaev et al., 2009)
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Summary

• Alzheimers Disease continues to afflict millions
  around the world
• No effective treatment
• Cause of AD still unknown, mechanisms unclear
• Expected to be an even bigger problem with the
  baby boomer generation growing older
• APP seems to be central to the development of AD
• Recent evidence suggests that APP can bind DR6 to
  elicit neuron death.

(Alzheimers Association, 2008)
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Literature Cited

• Nikolaev A, McLaughlin T, OLeary DD,
  Tessier-Lavigne M. 2009. APP binds DR6 to trigger
  axon pruning and neuron death via distinct
  caspases. Nature 457(7232)981-9
• John H and Dennis JS. 2002. The amyloid
  hypothesis of Alzheimers Disease progress and
  problems on the road to therapeutics. Science
  297353-6
• Alzheimers Association, 2008 Alzheimers Disease
  Facts and Figures, published in Volume 4, Issue
  2. Alzheimer's Dementia
• Van Broeck B, Van Broekhoven C, Kumar-Singh S.
  2007. Current insights into molecular mechanisms
  of Alzheimer disease and their implications for
  therapeutic approaches. Neurodegenerative
  Disorders 4(5)349-65
• Waring SC, Rosenberg RN. 2008. Genome-wide
  association studies in Alzheimers disease. Arch
  Neurol 65(3)329-34
• Thinakaran G, Koo EH. 2008. Amyloid precursor
  protein trafficking, processing, and function. J
  Biol Chem 283(44)29615-9