Knowledge of what causes Alzheimer’s disease is vital for developing drugs to control and prevent this disorder. The protein amyloid beta in the brain has been linked to the development of Alzheimer’s, and much current research revolves around finding ways to control this protein and lessen its possibly damaging effects.
Understanding Amyloid Beta
Amyloid beta is produced from the amyloid precursor protein, or APP, by the actions of enzymes called beta- and gamma-secretases. There are two main types of amyloid beta—AB40 and AB42—named according to their length. AB42 tends to amalgamate into a fibrous, insoluble form—known as a beta amyloid sheet—while AB40 becomes a more soluble form. Amyloid beta is normally produced at low levels and may be involved in signal regulation between brain cells called neurons; however, increases in this protein occur in those with Alzheimer’s.
Amyloid Plaques
One of the most distinguishing brain findings in Alzheimer’s are neuritic plaques outside of neurons mainly composed of clumps of beta amyloid sheets. However, their appearance does not correspond with the severity of Alzheimer’s and they can also be found in the brains of elderly people without the disease.
Amyloid Protective Processes
Although it was thought that amyloid plaques were always harmful in Alzheimer’s, they have been linked with protective processes. For instance, Math Cuajungco shows in the “Journal of Biological Chemistry” June 2000 edition that the fibrous form of amyloid beta is increased in response to a type of neuronal damage called oxidative stress and is involved in limiting that damage. It is the soluble form of amyloid beta, which occurs outside of plaques, that may be the damaging factor, as in Alzheimer’s, its appearance is much more in line with disease symptoms and neuronal damage.
Genes That Affect Amyloid
There are a number of genetic factors that can affect a person’s risk of developing Alzheimer’s, some of which lead to increases in the production of the fibrous form of amyloid beta. Mutations in the genes for APP can lead to the development of Alzheimer’s when a person is in his early 50s. Separate mutations in genes for components of the gamma-secretase enzyme can also lead to a disease onset between the mid 40s and late 50s.
Therapies Involving Amyloid
Current Alzheimer’s therapies revolve around increasing levels of brain chemicals lowered due to neuronal damage. Newer therapies are being developed that directly target amyloid beta. One of these, called LY450139/semagacestat, inhibits gamma-secretase, thus stopping the formation of amyloid beta. A study by Randall Bateman and colleagues in the “Annals of Neurology” July 2009 edition shows that this drug can decrease levels of amyloid beta in healthy people, so it is now being trialed in those with Alzheimer’s.
Another class of drug involves producing antibodies that bind to and clear already formed beta-amyloid plaques. These can successfully reduce the number of plaques in some patients. However, problems have occurred with this approach, including a brain inflammatory reaction in some patients in a trial of the drug AN-1792, and results only being limited to those with a mutation in a gene called ApoE4, with the drug bapineuzumab.
References
- “Current Opinion in Psychiatry"; Plasma Biomarkers of Alzheimer’s Disease; Takeshi Kawarabayashi and Mikio Shoji; May 2008
- “Acta Neuropathologica"; Classification and Basic Pathology of Alzheimer’s Disease; Charles Duyckaerts et al; July 2009
- “Journal of Biological Chemistry"; Evidence That the Beta-Amyloid Plaques of Alzheimer’s Disease Represent the Redox-Silencing and Entombment of Abeta by Zinc; Math Cuajungco; June 2000
