Alzheimer%20Disease

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Alzheimer Disease
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The year 2006 is the centenary of the famous
presentation of Alois Alzheimer which first
described the neuropathology of Alzheimers
disease (AD).

• Alzheimer described the results of his postmortem
  studies on a 51-year-old-female patient known as
  Auguste D., who had suffered from a progressive
  presenile dementia
• Described a relatively young patient who had
  developed a rapid loss of memory and had become
  disoriented in time and space.

Alois Alzheimer (b. 1864d. 1915)
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Alois Alzheimer

• As the illness progressed, she became bedridden
  and incontinent. She died four and a half years
  after the onset of illness.
• Post-mortem examination revealed an evenly
  atrophic brain with striking neurofibrillary
  pathology.
• Alzheimer also described the presence of unusual
• deposits in the cortex that were refractory to
  staining.

His famous paper (Alzheimer 1907)
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Alzheimers Disease

• Alzheimers disease is the most common form of
  dementia. accounting for 5060 of all cases.
• Dementia is a syndrome that exhibits impaired
  short-term and long term memory as its most
  prominent feature.
• Forgetfulness is the primary complaints of
  patients.

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Cholinergic hypothesis

• The cholinergic hypothesis in Alzheimers disease
  states that degeneration of cholinergic neurons
  in the basal forebrain nuclei causes disturbances
  in presynaptic cholinergic terminals in the
  hippocampus and neocortex, which is important for
  memory disturbances and other cognitive symptoms.
• Potentation of the activity of the central
  cholinergic pathway is one strategy for the
  symptomatic treatment of cognitive dysfunction in
  AD.

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Acetylcholinesterase inhibitorsTacrine

• Tacrine, the first agent approved for symptomatic
  treatment of mild to moderate AD
• Inhibit both acetylcholineesterase and
  butyrylcholineesterase (BuCHE)
• Low bioavailability, short half-life (multiple
  doses)

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Tacrine

• Side effect
• Nausea, vomiting , diarrhea, abdominal pain.
• Elevation of alanine aminotransferase (ALT) levels

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Donepezil

• Second generation cholinesterase inhibitors
• Selective Acetylcholinestearse than (BuCHE)
• Completely bioavailability, once daily
• Side effect cholinergic activity (nausea,
  diarrhea, headache)

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Rivastigmine

• Inhibit activity of both AChE and BuChE by
  binding to esteratic site of both enzymes and
  slowly dissociates.
• Called Pseudo-irreversible
• Twice daily

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Galantamine

• Inhibit AChE.
• allosteric modulation of nicotinic acetylcholine
  receptors
• It stimulates nicotinic receptors at a site
  distinct from that stimulated by acetylcholine
  action that does not rely on the presence of Ach
• Metabolized by CYP2D6

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Glutamate theory

• Glutamate is the major excitatory
  neurotransmitter in the central nervous system.
• An over activation of glutamate receptors, and
  particularly of N-methyl-D-aspartate (NMDA)
  receptors, leads to an immediate rise in calcium
  ions (cell death)
• Memantine blocks glutamate-mediated
  excitotoxicity

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Glutamate theory

• Memantine was approved for the treatment of
  moderate and severe AD case as early as in
  February 2002.
• The basis for this approval was the result of two
  randomized placebo-controlled clinical studies
  that have showed a positive effect in a later
  stage of this disease (Reisberg et al. 2003).
• It only affects pathophysiological conditions
  (NMDA receptor over activation) and leaves
  physiological neurotransmission unchanged.

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The amyloid cascade hypothesis

• Amyloid precursor protein (APP) is a protein
  containing 770 amino acids
• Cleaved into peptides by three enzymes alpha,
  beta and gamma secretase.
• APP is mainly formed by a two step process

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If alpha secretase initially cleaves APP,
alpha-soluble APP (a-sAPP) is formed and
eventually becomes a benign peptide.
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When beta secretase initially cleaves APP, it
becomes beta soluble APP (ß-sAPP). ß -sAPP can
subsequently be cleaved by gamma secretase at two
different sites producing harmful peptides such
as Ab 40 and Ab 42.
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The amyloid cascade hypothesis

• There are two types of beta secretase beta-site
  APP cleaving enzyme 1,2 (BACE 1, BACE 2)
• Two forms of gamma secretase (presenilin 1,
  presenilin 2).

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Alzheimer and genetics

• Less than 10 of the AD cases are autosomal
  dominantly inherited and are linked to one of
  three different chromosomes.
• To date, mutations in the following genes have
  been described to be causative for AD
• presenilin-1 gene on chromosome 14,
• presenilin-2 gene on chromosome 1
• amyloid precursor protein gene on chromosome 21.

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Alzheimer and genetics

• People that carry mutations in any one of these
  genes usually experience a very early onset of
  AD, well below 60 years of age

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Potential target in the future

• ß-secretase inhibitors
• ?-Secretase inhibitors

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Metal Ions and Amyloid ß proteins

• Aß itself can act as a metalloprotein displaying
  high affinity for copper (Cu2) and zinc (Zn2).
• Interaction between amyloid and metal ions might
  mediate amyloid aggregation and amyloid nerve
  cell toxicity

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Ion chelators

• clioquinol is a hydrophobic compound that acts
  as a copper and zinc chelator
• It can readily cross the blood brain barrier
• Clioquinol was used decades ago as an oral
  antiamoebic compound, but it has been withdrawn
  from the market because of possible neuropathic
  side-effects.
• Phase II clinical trial

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Disease-related changes of the tau

• tau is a protein involves binding and
  stabilization of microtubule structure and
  function.
• The microtubule network in the cell is required
  for the transport of proteins.

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Tau, calpains and apoptosis

• cyclin-dependent kinase 5 (cdk5), which promote
  phosphorylation of tau
• p35 is a neuron-specific activator of cdk5
• conversion of p35 into p25 by calpain-dependent
  proteolysis causes prolonged activation and
  mislocalization of cdk5.
• Consequently, the p25 / cdk5 kinase
  hyperphosphorylates tau, disrupts the
  cytoskeleton, and promotes apoptosis of primary
  neurons.

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Tau, calpains and apoptosis

• preaggregated Aß induced the generation of a
  neurotoxic 17-kDa tau fragment
• prevented by a calpain inhibitor
• Prevented by anti-tau.

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Apolipoprotein E4 (ApoE4)

• Approximately 15 of the human population inherit
  an allele, apolipoprotein E4 (ApoE4) which can
  increase the risk for AD by approximately 3-fold
  .
• The APO E gene comes in three flavors, the
  epsilon 2, epsilon 3 and epsilon 4 alleles.

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Apolipoprotein E4 (ApoE4)

• In healthy people, the frequency of the epsilon 4
  allele is 10 in AD patients, this frequency is
  increased to over 40.
• The existence of one or two copies of the epsilon
  4 allele increases of the AD onset in a
  dose-dependant manner

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Apolipoprotein E4 (ApoE4)

• This allele increases cholesterol concentrations
  and may be responsible for augmenting the amount
  of Aß or decreasing its clearance (4, 5).
• the formation of myelin is dependent on
  cholesterol, it has been suggested that
  cholesterol may be partially responsible for the
  progression of AD

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Statins for Alzheimer

• Medications which inhibit 3-hydroxy-3-methylglutar
  yl- coenzyme A (HMG-CoA) reductase have been
  proven to reduce serum cholesterol, and low
  density lipoproteins (LDL)
• lovastatin, simvastatin and cerivastatin cross
  BBB reduce the amount of Aß peptides by reducing
  cholesterol from the blood and/or the
  cerebrospinal fluid (CSF)

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Anti-inflammatory

• Inflammation is also occurring during the
  development of AD (Rogers et al. 1992 Akiyama et
  al. 2000).
• senile plaques attracting activated microglia,
  reactive astrocytes, cytokines and complement
  components (Akiyama et al. 2000)
• Reduction in the risk of AD associated with a
  chronic use of non-steroidal anti-inflammatory
  drugs (NSAID) ibuprofen, indomethacin and
  sulindac but no other NSAID decrease the
  release of Aß

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Treatment of behavioural signs

• Behavioural signs, such as aggression,
  psychomotor agitation, and psychosis
  (hallucinations and delusions)
• Atypical antipsychotic drugs

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Dementia and Alzheimer's disease

• Alzheimer's disease (AD) is a common age-related
  dementia, distinct from vascular dementia
  associated with brain infarction.
• The main pathological features of AD comprise
  amyloid plaques, neurofibrillary tangles and a
  loss of neurons (particularly cholinergic neurons
  of the basal forebrain).
• Amyloid plaques consist of the Aß fragment of
  amyloid precursor protein (APP), a normal
  neuronal membrane protein, produced by the action
  of ß- and ?-secretases. AD is associated with
  excessive Aß formation, resulting in
  neurotoxicity.

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• Familial AD (rare) results from mutations in the
  genes for APP, or the unrelated presenilin, both
  of which cause increased Aß formation.
• Neurofibrillary tangles comprise aggregates of a
  highly phosphorylated form of a normal neuronal
  protein (Tau). The relationship of these
  structures to neurodegeneration is not known.

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• Loss of cholinergic neurons is believed to
  account for much of the learning and memory
  deficit in AD.
• Anticholinesterases (tacrine, donepezil,
  rivastigmine) give proven, though limited,
  benefit in AD.

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• Many other drugs, including putative vasodilators
  (dihydroergotamine), muscarinic agonists
  (arecoline, pilocarpine ) and cognition enhancers
  (piracetam, aniracetam), give no demonstrable
  benefit and are not officially approved.
• Certain anti-inflammatory drugs, and also
  clioquinol (a metal chelating agent), may retard
  neurodegeneration and are undergoing clinical
  evaluation.