CJD and all

• CJD can occur as an inherited disease or as a sporadic form
• A paper was published in April 1996 in the medical journal Lancet describing a study of 10 persons afflicted with Creutzfeld-Jakob disease (CJD)
• Creutzfeld-Jakob disease (CJD) is a rare, fatal disorder that attacks the brain, causing a loss of motor coordination and dementia
• CJD can also be acquired, with cases described in the 1996 Lancet paper being acquired from contaminated beef
• The contaminated beef that caused CJD was derived from cattle raised in England with a neurodegenerative disease known as "mad cow disease"
• Roughly 200 people have died of CJD acquired from contaminated beef
• Diseases that run in families can be traced to a faulty gene, while diseases acquired from a contaminated source can be traced to an infectious agent
• Observations by D. Carleton Gajdusek in the 1960s showed a fatal neurodegenerative disease called "kuru" contracted by the native population of Papua, New Guinea
• Extracts from the brain of a person who died from CJD injected into a laboratory animal caused a similar spongiform encephalopathy
• Patients with kuru showed a distinct pathology in their brains referred to as spongiform encephalopathy
• The modified version of the prion protein (PrPSc) accumulates within nerve cells, forming aggregates that kill the cells
• The infectious agent responsible for CJD was suggested by Stanley Prusiner in 1982 to be a protein called a prion
• The prion protein is encoded by a gene (PRNP) within the cell's own chromosomes
• PrPC and PrPSc have very different physical properties, with PrPSc forming insoluble fibrils resistant to enzymatic digestion
• CJD is a rare disease caused by a protein with unique infective properties
• PrPSc molecule


  Interacts with one another to form insoluble fibrils resistant to enzymatic digestion
• PrPC and PrPSc molecules can have identical amino acid sequences but differ in the way the polypeptide chain folds to form the three-dimensional protein molecule
• Conversion of PrPC to PrPSc

  An abnormal prion molecule (PrPSc) can bind to a normal protein molecule (PrPC) and cause the normal protein to fold into the abnormal form
• Appearance of the abnormal protein in the body starts a chain reaction where normal protein molecules are gradually converted to the misshapen prion form
• PrPC molecule


  Soluble in salt solutions and readily destroyed by protein-digesting enzymes
• Alzheimer’s disease (AD) is a common disorder affecting individuals over 65 years old, characterized by memory loss, confusion, and loss of reasoning ability
• CJD and AD are fatal neurodegenerative diseases that can occur in either an inherited or sporadic form
• Both CJD and AD involve fibrillar deposits of an insoluble material referred to as amyloid in the brain
• Research on AD has been dominated by the amyloid hypothesis, suggesting that the disease is caused by the production of the amyloid β-peptide (Aβ)
• Aβ42, a misfolded version of the Aβ peptide, has the greatest potential to cause damage to the brain in AD
• Aβ oligomers are considered most toxic to nerve cells in AD, attacking synapses and leading to nerve cell death
• The weak correlation between the number and size of amyloid plaques in the brain and the severity of the disease is the strongest argument against the amyloid hypothesis
• Causes of overproduction of Aβ42

  • Extra copies (duplications) of the APP gene
  • Mutations in the APP gene
  • Mutations in genes (PSEN1, PSEN2) that encode subunits of γ-secretase
• Persons with an inherited form of Alzheimer's Disease (AD) carry a mutation that leads to increased production of the Aβ42 peptide
• Aβ oligomers appear to attack the synapses in the brain, leading to the death of nerve cells
• Individuals with mutations leading to increased production of Aβ42 exhibit symptoms of the disease at an early age, typically in their 50s
• All mutations associated with inherited, early-onset forms of AD lead to increased production of Aβ42, supporting amyloid formation as the underlying basis of the disease
• All drugs on the market for the treatment of AD only manage symptoms and do not stop disease progression
• Animal models, particularly mice, are used to test potential therapies for AD
• A Phase I clinical trial of the Aβ42 vaccine was quickly approved after successful experiments on mice, focusing on safety and optimal dosage rather than effectiveness against the disease
• In 1995, researchers created a strain of mice with amyloid plaques in their brain by genetically engineering them to carry a mutant human APP gene, providing a valuable animal model for AD
• Research strategies for new drugs for AD

  • Prevent the formation of the Aβ42 peptide
  • Remove the Aβ42 peptide or amyloid deposits
  • Prevent the interaction between Aβ molecules to prevent the formation of oligomers and fibrillar aggregates
• In 1999, researchers found that immunizing mice with the Aβ42 peptide could block the formation of amyloid plaques and improve memory performance
• None of the subjects in two separate Phase I trials of the Aβ vaccine showed any ill effects from the injection of the amyloid peptide
• 6 percent of the subjects in the Phase II trial experienced a potentially life-threatening inflammation of the brain after receiving two injections of synthetic β-amyloid