Biological Basis of Downs Syndrome and Alzheimers Disease

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Biological Basis of Downs Syndrome and
Alzheimers Disease

• Trevor Phinney
• Alex Hansler

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Alzheimers Disease

• Neurodegenerative disease that appears in the
  later periods of life
• Age of onset between 40-90 years old
• Leading cause of cognitive dysfunctions
• Memory loss
• Dementia
• Deterioration of language fcuntions

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Biological Basis of AD

• Increased Beta-amyloid deposits
• Derived from App (amyloid precursor protein)
• Neurofibrillary tangles
• Increases in caspase activity
• Decreases in drebrin levels
• Presenilin Gene (PS-1) mutations
• ApoE gene

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Presenilin Gene

• Austosomal Dominant
• PS-1 and PS-2
• Structurally similar
• 40 mutations of PS-1 gene
• Only 2 mutations in PS-2
• On chromosome 14

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Presenilin Gene(cont)

• PS-1 mutations lead to early onset AD symptoms
• Initially 70 of early-onset AD was a result of
  PS-1 mutation, but this is now considered an
  overestimate
• It is still a major locus for autosomal dominant
  AD mutations
• PS-2 lead to later onset AD
• PS-1 mutations are more common than both PS-2 or
  App mutations

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Apolipoprotein E (ApoE)

• ApoE is located on chromosome 19
• Binds to the beta-amyloid (AB) peptide (main
  component of neuritic plaques)
• It is present in senile plaque
• Indicates role as a possible pathological
  chaperone
• It has three common alleles (? 3, 4, 2)
• Have an effect on the age of onset
• Not know is loss or gain of function of ApoE that
  influences AD

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Downs Syndrome

• Trisomy 21
• Extra 21st chromosome due to non-disjunction
• Most frequent cause of mental retardation
• 1 out of 800 live births
• Associated with lower levels of cognitive and
  language functioning

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Biological Hypothesis of Both AD DS

• Increased Beta-amyloid (AB) deposits
• Neurofibrillary tangles
• Increases in caspase activity
• Causes neuronal cell death (apoptosis)
• Leads to increases in Beta-amyloid
• Drebrin abnormalities

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Beta-Amyloid (AB)

• Core protein of neuritic plaques
• Derived from a transmembrane glycoprotein,
  amyloid B precursor protein (APP)
• APP gene is located on the 21st chromosome
• DS has three 21st chromosome so the APP level is
  increased
• No correlation between the amount of AB and the
  severity of the phenotype

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Plaques

• Caused by the presence of accumulation of
  beta-amyloid in association with ApoE
• Three types
• Neuritic- radial fashion plaques surrounded by
  abnormally found dendrites and axons
• Diffuse plaques- more spread out deposits of AB
• End-stage plaques- remnants of old plaques

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Neurofibrillary Tangles (NFT)

• Parallel aggregates of thicken fibrils wound in a
  helical fashion
• Frequently surround the nucleus and extent
  towards apical dendrite
• Ghost tangles are seen that do not associate
  with any neurons
• Believed to be indicative of neurons that have
  already died from NFTs

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Neurofibrillary Tangles (cont)

• Microtubule associated protein Tau
• Primary constituent of the NFTs

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Caspases

• Only activated during Apoptosis
• Activation indicates presence of programmed cells
  death
• Cleaves proteins

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Caspases (cont)

• Caspase-8 play initiator role in apoptosis
• Appears to activate other downstream caspases
  that have direct effects on cell death
• Caspace activity has been found to be related to
  AB deposition
• May account for accumulation of AB
• May also contribute to the formation of NFTs

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Drebrin

• Closely related to the development of the brain
• Found in dendritic spines
• Associated with microtubules and may aide in
  growth of nueronal projections
• Expression levels of drebrin decreased in AD and
  DS patients
• Reduced in temporal and frontal cortex
• Not significantly reduced in the cerebellum

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Drebrin (cont)

• Reduction may lead to disorganization of actin
  filament dynamics and perhaps apoptosis
• Decreases cause abnormalities in dendritic
  spines of neurons

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Correlation between AD and DS

• Individuals with DS develop AD like brain
  abnormalities we discussed after the age of 40
• Increased Beta-amyloid (AB) deposits
• Neurofibrillary tangles
• Increases in caspase activity
• Drebrin abnormalities
• Studies of young vs. old DS patients
  distinguished it was an age effect

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How is this information useful?

• You can test a middle aged brain for increased AB
  deposits/caspase activity/decreased drebrin/etc.
  to determine likelyhood of developing AD.
• This shows neuroplasticity in the brain
• DS patients dont exhibit biological markers
  until after the age of 40