Amyloid Deposition in The Alzheimer Brain Is it The Cause of Dementia or an Epiphenomenon

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Amyloid ß Deposition in The Alzheimer BrainIs it
The Cause of Dementia? or an Epiphenomenon?

• Sami I. Harik, MD
• Professor Chairman of Neurology
• University of Arkansas College of Medicine

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I know that most men, including those at ease
with problems of the greatest complexity, can
seldom accept even the simplest and most obvious
truth if it be such as would oblige them to admit
the falsity of conclusions which they have
delighted in explaining to colleagues, which they
have proudly taught to others, and which they
have woven, thread by thread, into the fabric of
their lives. Leo Tolstoy
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Brain Atrophy in AD
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Alzheimer DiseaseThe Disease of The Century

• In 1907, Alois Alzheimer used novel histological
  stains to study the brain of a 51 year old
  patient with a progressive fatal dementia. The
  micropathologic cardinal features (i. e. markers)
  were
• PLAQUES, neuritic, senile, etc
• Neurofibrillary tangles.

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Histopathologic Markers of AD
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Amyloid ß is Part of The Plaque

• Left plaque amyloid white, microglia black,
  astrocytes brown.
• Right plaque amyloid brown, microglia black.

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Aß Plaques Capillaries
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Neuropathophysiology of AD

• Brain atrophy.
• Brain cell loss, mostly neurons.
• Major loss in connectivity, i.e. synapses.
• Losses in neurotransmitter functions.
• Hypometabolism low blood flow CMRgluc.
• Inflammation, cytokines.
• Membrane abnormalities, oxidative stress.

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The Hypothesis Became DogmaThe Amyloid ß Cascade
Story
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The Amyloid ß Cascade Story

• For the past 15 years, this hypothesis dominated
  AD research, unfortunately to the exclusion of
  other important leads.
• This domination was spurred by genetic findings
  of familial AD, and by the development of an
  animal model of AD with excess amyloid precursor
  protein production.

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The Genetic Findings in FAD

• ßAPP mutations (chromosome 21) result in
  increased production of amyloid ß protein.
• ApoE4 polymorphisms (chromosome 19) are
  associated with high brain plaque density.
• Presenilin 1 2 mutations (chromos 14 1)
  result in increased production of amyloid ß
  protein via decreased ? secretase activity.
• ßAPP presenilin 1 2 mutations, all account
  for lt 0.1 of AD population.

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Animal Models

• Several strategies employing genetic
  manipulations were used to produce experimental
  animals with heavy amyloid ß deposits in their
  brains, even more extensive than in AD subjects.
• These animals did not replicate the range of
  human AD pathology nor the dementia.

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The ß Amyloid Precursor Protein
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Consequences of The Dominant Hypothesis

• Much effort was given to development of methods
  to decrease ß amyloid deposition in the brain by
• Drugs that can modify APP a, ß and ? secretase
  enzymes. Thus far, there are no good news on this
  front.
• Vaccine that can dispose of ß amyloid in the
  brain. This already was found to be a disaster.

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Amyloid ß in Brain What Does it Do?

• There are 2 schools of thought
• 1. It is highly toxic, and the cause of AD
  pathology. This is the party line in AD circles.
• 2. It is a nonspecific marker of brain injury,
  and it is either
• An innocent bystander
• A protective and helpful agent
• 2 supporters cite presence of brain amyloid ß
  after trauma and inflammatory insults.

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Plaques Alzheimer Disease

• Studies of aged and middle-aged brains reveal
  that plaques with amyloid ß deposits are often
  present in cognitively intact people.
• There is only a weak correlation between amyloid
  ß burden on one hand, with neuronal loss and
  cognitive status on the other hand.
• There is a strong correlation between the density
  of tangles and cognitive functions.
• Hence, plaques are better than tangles.

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Is Amyloid ß Toxic?

• In cell culture studies, Aß IS toxic.
• In transgenic animal studies, Aß is NOT toxic.
• In normal human ageing, Aß is NOT toxic.
• Conclusion
• Cells in culture are not a good model for
  Alzheimer disease.

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Is Aß The Cause of AD or Simply An Epiphenomenon?
ßAPP/PS
Aß
AD
or
AD
ßAPP/PS
???
Aß
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The Amyloid ß Vaccine

• Most investigators were pleased when transgenic
  mice with increased brain Aß load were given Aß
  vaccine to rid their brains of toxic Aß.
• Patients with AD can be vaccinated, and the
  controversy as to whether Aß is toxic can be
  settled.
• Unfortunately, human Aß vaccination had to be
  stopped because of worsening of several subjects.

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• Amyloid ß may be protective against the ravages
  of ageing and oxidative stress

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