AMYLOID PRECURSOR PROTEINS PROTECT NEURONS OF TRANSGENIC MICE AGAINSTACUTE AND CHRONIC EXCITOTOXIC INJURIES IN-VIVO

The beta-amyloid protein precursor (APP) is well conserved across diff erent species and may fulfill important physiological functions within the CNS. While high level neuronal expression of amyloidogenic forms of human APP results in beta-amyloid production and neurodegeneration, lower levels of neuronal human APP expression in neurons of transgeni c mice may primarily accentuate physiological functions of this molecu le. To assess the neuroprotective potential of human APP in vivo, mice from seven distinct transgenic lines expressing different human APP i soforms from the neuron-specific enolase promoter were challenged with systemic kainate injections (n=30) or transgene-mediated glial expres sion of gp120 (n=32), an HIV-1 protein capable of inducing excitotoxic neuronal damage. To quantitate human APP-mediated neuroprotection, th e area of neuropil occupied by presynaptic terminals and neuronal dend rites in the neocortex and hippocampus of each mouse was determined us ing laser scanning confocal microscopy of double-immunolabelled brain sections and computer-aided image analysis. Compared with gp120 singly transgenic controls, mice from three of three human APP751/gp120 bige nic lines expressing the 751 amino acid form of human APP at low level s showed significant protection against degeneration of presynaptic te rminals; two of these lines also showed significantly less damage to n euronal dendrites. Two of three human APP695/gp120 bigenic lines expre ssing human APP695 at low levels were protected against presynaptic an d dendritic damage, whereas one low expressor line and a human APP695/ gp120 bigenic line expressing human APP695 at higher levels showed no significant protection. In the corresponding human APP singly transgen ic lines, overexpressing only specific human APP isoforms, significant protection against kainate-induced degeneration of presynaptic termin als and neuronal dendrites was found in two of three human APP751 line s and not in any of the four human APP695 lines tested. These results indicate that human APP can protect neurons against chronic and acute excitotoxic insults in vivo and that human APP isoforms differ in thei r neuroprotective potential, at least with respect to specific forms o f neural injury. It is therefore possible that impairments of neuropro tective human APP functions or aberrant shifts in human APP isoform ra tios could contribute to neurodegeneration. (C) 1997 IBRO.