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Alzheimer's disease


Alzheimer's disease. Beta amyloid protein and the potential for anti-oxidants drugs. Approximately 4.5 million people in the ... Pathophysiology of Alzheimer's ... – PowerPoint PPT presentation

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Title: Alzheimer's disease

Alzheimer's disease
  • Beta amyloid protein and the potential for
    anti-oxidants drugs

  • Approximately 4.5 million people in the U.S. have
    Alzheimers disease (AD). It is the 4th or 5th
    leading cause of death.
  • The prevalence is 3 for persons 65-74 years old,
    19 for those 75-84 years old and 47 for those
    over 85 years old.
  • The cost of care for patients with Alzheimers
    disease in the U.S. is 83.9 billion annually (in
    1996 dollars) and rising.
  • With the aging U.S. population, the number of
    people in the U.S. with Alzheimers disease is
    expected to rise to 9 million by 2040.

  • Current therapies have extremely limited
    efficacy, with a typical benefit of 6 to 12
    months delay in the progression of symptoms.
  • Evidence that oxidative damage occurs in patients
    with mild cognitive impairment (MCI), a precursor
    of Alzheimers, may provide more opportunities
    for an anti-oxidant compound.

Pathophysiology of Alzheimers
  • In a 2004 review on Alzheimers disease in the
    New England Journal of Medicine, Jeffrey Cummings
    described current knowledge of the
    pathophysiology of Alzheimers (Cummings 2004)

  • There is increasing consensus that the production
    and accumulation of beta-amyloid (AB) peptide is
    central to the pathogenesis of Alzheimers
  • Evidence for a pivotal role for AB includes the
    following mutations in the amyloid precursor
    protein lead to early-onset Alzheimers disease
  • All currently known mutations associated with
    Alzheimers disease increase the production of AB

  • In patients with trisomy 21 (Downs syndrome) and
    three copies of the gene for amyloid precursor
    protein, neuropathological characteristics of
    Alzheimers disease develop by midlife AB is
    neurotoxic in vitro and leads to cell death

  • Overexpression of human amyloid precursor protein
    in transgenic mouse models of Alzheimers disease
    results in neuritic plaques similar to those seen
    in humans with Alzheimers disease

  • Transgenic mice overexpressing the human amyloid
    precursor protein have evidence of learning and
    memory deficits, in concert with the accumulation
    of amyloid the apolipoprotein E4 genotype, a
    major risk factor for Alzheimers disease, leads
    to accelerated deposition of amyloid and the
    generation of antiamyloid antibodies in humans
    with Alzheimers disease seems to ameliorate the
    disease process.

  • Formation of neurofibrillary tangles, oxidation
    and lipid peroxidation, glutamatergic
    excitotoxicity, inflammation, and activation of
    the cascade of apoptotic cell death are
    considered secondary consequences of the
    generation and deposition of AB.
  • This hypothesized amyloid cascade underlies
    attempts to modify the onset and course of
    Alzheimers disease through identification of
    antiamyloid agents, antioxidants, and other drugs

  • Alternate hypotheses regarding the
    pathophysiology of Alzheimers disease place
    greater emphasis on the potential role of
    tau-protein abnormalities, heavy metals, vascular
    factors, or viral infections.

  • There are many studies of the role of oxidative
    stress in Alzheimers disease and more
    specifically the activity of AB in production of
    reactive oxygen species (ROS).
  • Evidence supporting the role of AB and oxidative
    stress in Alzheimers disease includes the

  • Amyloid beta generates free radicals
  • The Met35 amino acid residue of AB is responsible
    for free radical production

Researchers have found a variety of oxidative
damage in AD brains
  • increased lipid peroxidation and decreased
    polyunsaturated fatty acids in the AD brain, and
    increased 4-hydroxynonenal, an aldehyde product
    of lipid peroxidation in AD ventricular fluid
  • increased protein and DNA oxidation in the AD
    brain diminished energy metabolism and decreased
    cytochrome c oxidase in the brain in AD
  • advanced glycation end products (AGE),
    malondialdehyde, carbonyls, peroxynitrite, heme
    oxygenase-1 and SOD

  • Oxidative damage appears to be one of the
    earliest pathophysiological events in Alzheimers
    preceding the formation of amyloid plaques and
    neurofibrillary tangles.
  • Plasma levels of most antioxidants are lower in
    patients with Alzheimers and Mild Cognitive
    Impairment (MCI) compared to healthy age-matched

  • Transgenic mice expressing AB reproduce the
    clinical symptoms and pathological progression of
    AD including oxidative stress.
  • In beta-amyloid transgenic mice, memory
    impairment is correlated with increased levels of
    beta amyloid
  • Active and passive beta-amyloid-directed
    immunization removes beta-amyloid plaques and
    restores memory.

  • In transgenic mice expressing both AB and
    presenilin 1, gene expression profiles using
    microarrays and Q-PCR showed reduced expression
    of genes required for long-term potentiation and
    memory formation.
  • In studies of cortical tissue AD patients, the
    same memory-associated genes are down-regulated.

  • Numerous studies have shown that free radicals
    cause neuron degeneration and death in vitro and
    in vivo, while anti-oxidants have been shown to
    protect against neurodegeneration and have shown
    efficacy in clinical trials for treating
    Alzheimers disease and in epidemiologic studies
    for reducing the risk of Alzheimers disease

not proven that AB or ROS directly cause
Alzheimers disease.
  • Because tissue injury itself can induce reactive
    oxygen species (ROS) generation, it is not known
    whether this is a primary or secondary event in
    Alzheimers disease. Even if free radical
    generation is secondary to other initiating
    causes, they are deleterious and part of a
    cascade of events that can lead to neuron death,
    suggesting that therapeutic efforts aimed at
    removal of ROS or prevention of their formation
    may be beneficial in AD (Markesbery 1997).

  • Many but not all anti-oxidants have been shown to
    cross the blood-brain barrier and to have
    neuroprotective effects in vitro and/or in vivo
    in humans or in animal models.
  • The major limitations of these anti-oxidants
    appear to be their relatively short half-life in
    vivo (ALA), their (possibly) relatively low
    bioavailability at the sites of free-radical
    production (Vitamins C and E) and the lack of
    patent protection.

Alzheimers drug development
  • Many pharmaceutical companies are pursuing new
    treatments for Alzheimers, with a wide variety
    of targets, including AB and anti-oxidants.
  • In a 2004 NEJM review, Cummings describes current
    research on treatments of Alzheimers

Antiamyloid therapies
  • No antiamyloid therapies are currently available.
  • The enzymes responsible for liberating AB, a
    toxic fragment of 42 amino acids, from the
    amyloid precursor protein are b and g secretases.
    Inhibitors of these enzymes are under active
  • The metabolism of cholesterol is intimately
    involved in the generation of AB, and preliminary
    evidence suggests that statins may be beneficial
    in reducing the accumulation of AB.

Neuroprotective approaches
  • AB protein seems to exert its neurotoxic effects
    through a variety of secondary mechanisms,
    including oxidative injury and lipid peroxidation
    of cell membranes, inflammation,
    hyperphosphorylation of tau protein, and
    increased glutamatergic excitotoxicity.
  • Neuroprotective strategies have targeted these
    mechanisms in an effort to reduce the cell injury
    associated with the generation and aggregation of

  • The principal antioxidant strategy has involved
    treatment with alpha-tocopherol (vitamin E).
  • A randomized, placebo-controlled trial compared
    the effect of vitamin E, selegiline, the two
    drugs together, and placebo in patients with
    Alzheimers disease.

  • When the severity of cognitive decline at
    baseline was included as a covariate, a
    significant delay in the primary outcomes (time
    to death, placement in a nursing home,
    development of severe dementia, or a defined
    severity of impairment of activities of daily
    living) was observed for patients in the
    selegiline, alpha-tocopherol, and
    combination-therapy groups, as compared with the
    placebo group.

  • The increase in median time to one of the primary
    outcomes, as compared with the time in patients
    receiving placebo, was 230 days for patients
    receiving alpha-tocopherol, 215 days for those
    treated with selegiline, and 145 days for those
    receiving both agents.
  • No differences in cognitive function were evident
    among the four groups.

  • On the basis of this study, many practitioners
    have added high-dose vitamin E supplements (2000
    IU daily) to their standard treatment regimen for
    Alzheimers disease.

Rutten review of antioxidant clinical trials in
Alzheimers disease
  • Recent prospective studies have indicated that
    dietary intake of several exogenous antioxidants
    is associated with a lower risk for Alzheimer's
  • This suggests that people at risk for developing
    Alzheimer's disease or being in the early phases
    of this disease may benefit from intervention
    with exogenous antioxidants.
  • The clinical studies carried out so far, however,
    do not provide the final answer to whether
    antioxidants are truly protective against
    Alzheimer's disease

  • There is compelling evidence that oxidative
    stress is involved in Alzheimer's disease
    pathogenesis, and several lines of evidence
    indicate that administration of antioxidants may
    be useful in prevention and treatment of
    Alzheimer's disease.
  • Further clinical studies, based on larger cohorts
    studied over a longer period of time, are needed,
    however, to test this hypothesis.
  • Furthermore, for the future one might expect
    balanced upregulation of both exogenous and
    endogenous antioxidants as one of the best
    treatment strategies for preventing or at least
    slowing down the progression of Alzheimer's