[Molecular mechanisms in Alzheimer's disease].

15.1 Introduction Alzheimer's disease (AD), a progressive neurovegetative disorder of the central nervous system and a leading cause of dementia, is partially caused by genetic changes. The molecular mechanisms and hypothesis of AD is very complex. The key event leading to AD appears to be the formation of a peptide known as amyloid beta (Aß) which clusters into amyloid plaques or senile plaque on blood vessels and on the outside surface of neurons of the brain, which ultimately leads to the killing of neuron. Amyloid cascade of events in AD would be: Aß formation → amyloid plaques → neuron death → dementia The amyloid ß-peptide is created by enzyme clipping of the neuron membrane protein known as amyloid precursor protein (APP). Enzymes can clip APP in the ways that do not result in amyloid ß formation. Moreover, there are two forms of amyloid ß-peptide, one with 40 and other with 42 aminoacids. The 42 amino acid peptide is more hydrophobic than that with 40. Following amyloid plaque formation, two processes play an important role in causing the death of neurons: inflammation and neurofobrillary tangles. Two major types of brain cells that participate in immune and inflammatory process are astrocytes and microglia. The number of astrocytes seems to be enlarged in AD and activated to produce prostaglandin leading to arachidonic acid mediated inflamation. Furthermore, activated microglial cells produce free radicals and this mechanism leads to the death of neurons. Neurons can be very large and nutrient substances as well as cell regulation components are transported along microtubules. Structural integrity of microtubules is maintained by tau protein. In AD, tau protein loses its capacity to bind to microtubules but binds to each other forming paired helical filaments forming knots known as neurofibrillary tangles (NFTs) which further cause microtubule death. With these facts in mind, the second part of the amyloid cascade would be: APP→ Aß42 → amyloid plaque → inflammation NFTs → neuron death. The formation of Aß42 from APP is regulated by secretases – two enzymes that compete to cleave APP and consequently cause formation of insoluble amyloid plaques. a-secretase cleaves APP in a way in which Aß42 is not formed. On the contrary, ß-secretase and, in the next step, ?-secretase cleaves APP forming either 40 aminoacid amyloid protein which is soluble, or 42 aminoacid amyloid peptide which clumps together forming insoluble amyloid plaques. Familial AD is genetically heterogeneous and appears …