Peptide fragments of beta-amyloid precursor protein: Effects on parallel fiber-Purkinje cell synaptic transmission in rat cerebellum

The effects of peptide fragments of the beta-amyloid precursor protein (bet a APP) on parallel fiber (PF)-Purkinje cell synaptic transmission in the ra t cerebellum were examined. Transient inward currents associated with calci um influx were induced by localized applications of the 105-amino acid carb oxy-terminal fragment (CT105) of beta APP to discrete dendritic regions of intact Purkinje cells. beta APP and the amyloid beta (A beta) peptide fragm ents AP(1-16), A beta(25-35), and A beta(1-42) had little or no effect. Inw ard currents were also observed following applications of CT105 to isolated patches of somatic Purkinje cell membrane. All five proteins/peptides indu ced some depression of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionat e (AMPA) receptor-mediated synaptic transmission between PFs and Purkinje c ells, through a combination of pre- and postsynaptic effects. CT105 induced the greatest depression, which spread to distant synapses following local application and which was prevented by inhibition of nitric oxide synthase. These data indicate that CT fragments of the beta APP can modulate AMPA-me diated glutamatergic synaptic transmission in the cerebellar cortex. These fragments may therefore be considered alternative candidates for some of th e neurotoxic effects of Alzheimer's disease.