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Mechanisms of Alzheimers Disease Amyloid Precursor Protein APP

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APP gives rise to -amyloid which is found in plaques ... The amyloid hypothesis of Alzheimer's Disease: progress and problems on the road ... – PowerPoint PPT presentation

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Title: Mechanisms of Alzheimers Disease Amyloid Precursor Protein APP


1
Mechanisms of Alzheimers Disease Amyloid
Precursor Protein (APP)
  • Ivan Millan

2
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)
3
Comparison of healthy brain and AD brain
  • Alzheimers patients exhibit progressive loss of
    neurons
  • Other physical symptoms include plaques and
    tangles

4
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)
6
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)
7
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

8
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).

9
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.

10
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)
11
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
12
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)
13
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)
14
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)
15
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
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