rried out. If there is no other cause for the symptoms, then a diagnosis of Alzheimer=s is made. Alzheimer=s is believed to occur due to the death of neuronal cells, and there is considerable evidence that the altered metabolism of beta-amyloid precursor protein (APP) and accumulation of its beta-amyloid fragment are key features of Alzheimer=s disease. However, the normal function of APP is unknown (Rohn et al, 2000).
Rohn used a monoclonal antibody 22C11, which binds to the extracellular domain of the human, rat, or mouse APP to study its role. Exposure of cortical neurons to 22C11 induced morphological changes including neurite degeneration, nuclear condensation, and internucleosomal DNA cleavage that were consistent with neurons dying by apoptosis. This supports a role for 22C11-mediated apoptosis occurring by binding to APP, since preincubation of 22C11 with either purified APP or a synthetic peptide (APP(66-81)) that contains the epitope for 22C11 significantly attenuated neuronal damage induced by 22C11.
These researchers also showed that mouse immunoglobulin G and the monoclonal antibody P2-1, which is specific for the amino terminal end of human but not rat APP, had no apparent effects on neuronal cells. Other features indicative of apoptosis were found: the formation of 120- and 150-kDa breakdown products of fodrin when cortical neurons were treated with 22C11, but pretreatment of the neurons with the general capsase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp)o-methyl)-fluoromethyl ketone, prevented both the morphological and the biochemical changes caused by 22C11. Also, prior incubation of cortical neurons with GSH ethyl ester (GEF), a cell-permeable form of GSH, resulted in complete protection from the 22C11 destruction, implicating an oxidative pathway in 22C11-mediated neuronal degeneration. This was further supported by pre-treatment of the neurons with buthionine sulfoximine, an inhibitor of gamma...