Peptide fragments of β-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 (beta APP) on parallel fiber (PF)-Purkinje cell synaptic transmission in the rat cerebellum were examined. Transient inward currents associated with calcium influx were induced by localized applications of the 105-amino acid carboxy-terminal fragment (CT105) of beta APP to discrete dendritic regions of intact Purkinje cells. beta APP and the amyloid beta (A beta) peptide fragments AP(1-16), A beta(25-35), and A beta(1-42) had little or no effect. Inward currents were also observed following applications of CT105 to isolated patches of somatic Purkinje cell membrane. All five proteins/peptides induced some depression of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor-mediated synaptic transmission between PFs and Purkinje cells, 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-mediated glutamatergic synaptic transmission in the cerebellar cortex. These fragments may therefore be considered alternative candidates for some of the neurotoxic effects of Alzheimer's disease.