SYNAPTOTROPHIC EFFECTS OF HUMAN AMYLOID-BETA PROTEIN PRECURSORS IN THE CORTEX OF TRANSGENIC MICE

The amyloid precursor protein (APP) is involved in Alzheimer's disease (AD) because its degradation products accumulate abnormally in AD bra ins and APP mutations are associated with early onset AD. However, its role in health and disease appears to be complex, with different APP derivatives showing either neurotoxic or neurotrophic effects in vitro . To elucidate the effects APP has on the brain in vivo, cDNAs encodin g different forms of human APP (hAPP) were placed downstream of the ne uron-specific enolase (NSE) promoter. In multiple lines of NSE-hAPP tr ansgenic mice neuronal overexpression of hAPP was accompanied by an in crease in the number of synaptophysin immunoreactive (SYN-IR) presynap tic terminals and in the expression of the growth-associated marker GA P-43. In lines expressing moderate levels of hAPP751 or hAPP695, this effect was more prominent in homozygous than in heterozygous transgeni c mice. In contrast, a line with several-fold higher levels of hAPP695 expression showed less increase in SYN-IR presynaptic terminals per a mount of hAPP expressed than the lower expressor lines and a decrease in synaptotrophic effects in homozygous compared with heterozygous off spring. Transgenic mice (2-24 months of age) showed no evidence for am yloid deposits or neurodegeneration. These findings suggest that APP m ay be important for the formation/maintenance of synapses in vivo and that its synaptotrophic effects may be critically dependent on the exp ression levels of different APP isoforms. Alterations in APP expressio n, processing or function could contribute to the synaptic pathology s een in AD.