Alzheimer's Research

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Alzheimer's Research

• Yesterdays Discoveries
• Todays Work
• Tomorrows Promise

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Knowledge and ignorance

• We don't know one-millionth of one percent about
  anything. - Thomas Edison
• "If artists and scientists share passion as a
  driving force, they also share the same energy
  emotion, a sense of wonder at the universe, this
  endless source of question marks."
• He who knows little, quickly tells it.

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Outline

• 1. How we learned what we know- The discoveries
  of yesterday
• 2. Our current state of knowledge, and the
  treatments available-the work of today
• 3. The drugs in testing for tomorrow, and what we
  can look forward to-The promise of the future

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Alois Alzheimer and Frau Auguste D

• Ive lost myself

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Amyloid Plaque
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Questions in 1907

• What are the plaques made of?
• Are they killing the neurons?
• After many decades of work-
• Plaques are formed mostly from a very small
  protein called Ab42, along with some other
  substances, including, oddly, high metal
  concentrations

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Cell Culture-Growing a brain in a dish
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Ab42 added to neurons kills them
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More questions

• How is the Ab42 made?
• How does Ab42 kill neurons?

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Molecular origin of Ab 1-42
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How does Ab42 harm neurons?Excess Calcium
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How does Ab42 harm neurons?Oxidative Damage
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Transgenic research

• Ab42 kills cells in culture, but can it cause a
  disease?
• Research in the 1990s led to ability to make
  transgenic animals-

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Brain from transgenic AD mouse
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The brain as part of a team

• At 3 lbs, the brain can use up to 25 of the
  oxygen and sugar in the blood
• The health of the brain is critically dependent
  on the health of the body-especially
• Cardiovascular health
• Metabolic state (Diabetes)

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Brain Activity
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Cardiovascular and cholesterol

• Risks High blood pressure, obesity, diabetes
• Special risk of cholesterol clearance in neurons-
  ApoE4

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AD Risk associated with ApoE isoform
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Summary of what we know

• Ab42 is made by a specific cut by the enzyme
  gamma secretase
• Ab42 then forms into insoluble waxy deposits
  called plaques
• These plaques are toxic to neurons, causing
• Increased calcium into the neuron
• Increased oxidative stress
• Inflammation
• This then causes the neuron to get sick, so that
  they release less neurotransmitter and
  communicate less
• Eventually, the neuron dies
• The ability of the neuron to resist this depends
  on poorly understood factors of metabolism and
  cholesterol
• ALL of these factors are targets for drug
  development

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Current Treatments

• In 1993- the FIRST drug released for AD
  treatment.
• Tacrine (Cognex)- Inhibited the breakdown of
  acetylcholine, by blocking the enzyme
  acetylcholinesterase
• Efficacious for mild to moderate Alzheimer's
  disease
• Very serious side effects, limited efficacy

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Cholinesterase Inhibitors
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Other Ach Inhibitors followed

• Acetylcholine esterase inhibitors
• Donepezil (Aricept) piperidine-based, reversible
  inhibition of its hydrolysis by
  acetylcholinesterase
• Galantamine (Razadyne ER/ Reminyl) a tertiary
  alkaloid, is a competitive and reversible
  inhibitor of acetylcholinesterase.
• Rivastigmine (Exelon ) carbamate-type,
• Do not improve underlying condition, do not
  increase lifespan

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In 2003, the first drug approved for severe AD-
Memantine

• Ebixa, Namenda Moderate-affinity NMDA
  (N-methyl-D-aspartate) receptor antagonist.
• Memantine seems to reduce the entrance of calcium
  through specific channels

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Memantine
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Non-prescription drugs

• NSAIDS (Aspirin, etc)- Reduce inflammation- delay
  onset and extend function
• Anti-oxidants (Vitamin E)- Reduce the oxidative
  damage
• Omega-3 fatty acids-May regulate cholesterol
  clearance and oxidative stress

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Developing a new drugClinical Trial

• Definition
• A prospective study that compares the effect and
  value of interventions against a control in human
  beings.

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Clinical Trials Process of Candidate Drug
Development to Obtain Approval for Patient
Prescription

• Phase 1 first administration to humans to
  determine the maximum tolerated dose and the
  toxicity in humans
• Phase 2 to determine the efficacy
• Dose regime and patient selection
• Find rate of common serious adverse effects
• Phase 3 test effectiveness
• Submission to the National Regulatory Body for
  evaluation and approval
• Phase 4 Long term observation following
  marketing of approved drug

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New breakthrough drugs are hard to find

• Only 10 of compounds reaching clinical trial
  make it to market
• It takes 10-12 yrs from discovery of new medicine
  until it is available to the patient
• The average cost for a medicine to get to market
  in 2002 was 800 million (USD)
• Only 3/10 new products recover development costs

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Drugs in Phase IIIFlurizan

• Binds to and modulates of g-secretase-Causes less
  Ab42, and more Ab40
• In this Phase 2 study, most patients were
  receiving acetylcholinesterase inhibitors, thus
  the results are above the current standard of
  care.
• In nonclinical studies, FLURIZAN reduced Ab42 by
  approximately 70
• Decrease in the number of psychiatric events and
  the dramatic lengthening in time before patients
  experienced such events

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Flurizan
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Flurizan Phase 2 trial
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Flurizan Phase 2 trial
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Flurizan Phase 2 trial
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Drugs in Phase IIINeurotrophic agents

• Xaliproden (SR 57746) and Cerebrolysin
• Neurotrophins are hormone-like molecules that aid
  neuronal health
• These drugs mimic natural neurotrophins and may
  increase neuronal resistance

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Drugs in Phase IIIAnti-inflammatories
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Ibuprofen (Advil, Motrin, Nuprin)

• Preventing or delaying the onset of Alzheimer's
  disease by decreasing inflammation in the brain
• A nonsteroidal anti-inflammatory drug (NSAIDs),
• NSAIDs help Alzheimer's patients have been
  retrospective.
• Reduces prostaglandin activity by inhibiting
  prostaglandin synthetase

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Estrogen (Premarin)

• estrogen in postmenopausal women may delay the
  onset or risk of AD.
• antioxidant and anti-inflammatory effects and
  enhances the growth of select neurons that
  release acetylcholine
• may improve lipoprotein/lipid metabolism.

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Vitamin E (Alpha-tocopherol )

• Good dietary sources of vitamin E include
  spinach, eggs, nuts and seeds, avocado, tomatoes,
  peaches, and blackberries
• recommended 400 IU of vitamin E daily
• did not appear to help people with a version of
  the apolipoprotein E (Apo E) ApoE4
• considered to be an anti-oxidant vitamin
• Also a know anticoagulant

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Drugs in Phase IIIZocor Lipitor

• Decreases cholesterol, LDL, triglycerides, and
  increases HDL
• Seem to inhibit both alpha and beta secretase
  activities in CNS.
• Also seem to decrease inflammation

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Zocor Lipitor
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Drugs in Phase IIIAvandia (rosiglitazone XR)

• Diabetes drug- Aids in regulation of blood sugar
• Appears to provide increased energy to neurons,
  allowing them to resist stress.
• Is not effective for those who carry the ApoE4
  gene linked to earlier and faster-progressing
  Alzheimer's disease.

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Avandia
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Drugs in Phase IIITramiprosate (ALZHEMED)

• Sticks to Ab42, and stops it from forming plaques
• Dose- dependently reduced CSF A(beta)42 levels
  after three months of treatment.
• Results consistent with stabilization of
  cognitive function in mild AD patients after up
  to 36 months.

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Tramiprosate (ALZHEMED)
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Special Topic Ab Vaccines

• In this process, a form of Ab, or of amyloid
  plaque, is injected into a person, to they have
  an allergic reaction
• Theoretically, antibodies are formed against the
  Ab, and this may help clear the plaque

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Ab vaccine
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How the vaccine may work
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Much left to do
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Percival Linc Aulston1907-1993

• Your greatest triumphs come when you think you
  are most alone.
• But, you are never really alone
• THANK YOU

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Nasal Spray

• Administered via drops in the nose -- that would
  initiate an amyloid-cleansing process by
  triggering the immune system without provoking
  antibody development.
• Targeted a specific type of amyloid-eating cell
  known as a microglial cell -- stimulating the
  cells into action to essentially gobble up the
  amyloid build-up.

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Innate immune response to amyloid-ß in
Alzheimers disease
Steps in the inflammatory process surrounding the
amyloid plaques are shown. The production of
complement components (C1q, C3 and C5) is the
first stage in response to amyloid-ß deposition,
followed by migration of microglial cells to the
brain. This is followed by astrogliosis, which is
characterized by increased expression of the
astrocyte marker glial fibrillary acidic protein
(GFAP) in the brain. Both microglial cells and
astrocytes secrete various pro-inflammatory
mediators that exacerbate the process.
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Clinical trials of amyloid-ß142 immunization

• An amyloid-ß142 synthetic peptide (AN1792 Elan
  Pharmaceuticals Inc.) was administered with a
  previously tested T helper 1 (TH1)-cell-inducing
  adjuvant (QS21) to individuals with mild to
  moderate Alzheimers disease.
• Intramuscular injection
• that nasal vaccination with a proteosome-based
  adjuvant that is well tolerated in humans plus
  glatiramer acetate, an FDA-approved synthetic
  copolymer used to treat multiple sclerosis,
  potently decreases Aß plaques in an AD mouse
  model. This effect did not require the presence
  of antibody, as it was observed in B
  celldeficient (Ig µnull) mice. Vaccinated
  animals developed activated microglia that
  colocalized with Aß fibrils, and the extent of
  microglial activation correlated strongly with
  the decrease in Aß fibrils. Activation of
  microglia and clearing of Aß occurred with the
  adjuvant alone, although to a lesser degree. Our
  results identify a novel approach to immune
  therapy for AD that involves clearing of Aß
  through the utilization of compounds that have
  been safely tested on or are currently in use in
  humans.

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Research Hope