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 i n 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 (beta APP) in the neurotoxicity assiciated with AD. We focused on the amyloidegenic carboxyl terminal fragments of beta APP con taining the full length of A beta (CT105). We synthesized a recombinant car boxyl-terminal 105 amino acid fragment of beta APP and examined the effects of CT105 and A beta on cultured neurons, Ca++ uptake into rat brain micros omes, Na+-Ca++ exchange activity, ion channel forming activity in lipid bil ayers and passive avoidance performance of mice. Our results suggest that the cytotoxic and channel inducing effects of CT10 5 are much more potent than that of A beta and toxic mechanisms of CT105 ar e 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.