Roles of A beta and carboxyl terminal peptide fragments of amyloid precursor protein in Alzheimer disease.

Several lines of evidence indicate that A beta may play an important role in the pathogenesis of AD. However, there are several discrepancies between the production of A beta and the development of the disease. Thus, A beta may not be the sole active fragment of beta-amyloid precursor protein (betaAPP) in the neurotoxicity assiciated with AD. We focused on the amyloidegenic carboxyl terminal fragments of betaAPP containing the full length of A beta (CT105). We synthesized a recombinant carboxyl-terminal 105 amino acid fragment of betaAPP and examined the effects of CT105 and A beta on cultured neurons, Ca++ uptake into rat brain microsomes, Na+-Ca++ exchange activity, ion channel forming activity in lipid bilayers and passive avoidance performance of mice. Our results suggest that the cytotoxic and channel inducing effects of CT105 are much more potent than that of A beta and toxic mechanisms of CT105 are different from those of A beta. Taken together, these lines of evidence postulate that CT is an alternative toxic element important in the generation of the symptoms common to AD.