High-level neuronal expression of A beta(1-42) in wild-type human amyloid protein precursor transgenic mice: Synaptotoxicity without plaque formation

Amyloid plaques are a neuropathological hallmark of Alzheimer's disease (AD ), but their relationship to neurodegeneration and dementia remains controv ersial. In contrast, there is a good correlation in AD between cognitive de cline and loss of synaptophysin-immunoreactive (SYN-IR) presynaptic termina ls in specific brain regions. We used expression-matched transgenic mouse l ines to compare the effects of different human amyloid protein precursors ( hAPP) and their products on plaque formation and SYN-IR presynaptic termina ls. Four distinct minigenes were generated encoding wild-type hAPP or hAPP carrying mutations that alter the production of amyloidogenic A beta peptid es. The platelet-derived growth factor beta chain promoter was used to expr ess these constructs in neurons. hAPP mutations associated with familial AD (FAD) increased cerebral A beta(1-42) levels, whereas an experimental muta tion of the beta-secretase cleavage site (671(M-->I)) eliminated production of human A beta. High levels of A beta(1-42) resulted in age-dependent for mation of amyloid plaques in FAD-mutant hAPP mice but not in expression-mat ched wild-type hAPP mice. Yet, significant decreases in the density of SYN- IR presynaptic terminals were found in both groups of mice. Across mice fro m different transgenic lines, the density of SYN-IR presynaptic terminals c orrelated inversely with A beta levels but not with hAPP levels or plaque l oad. We conclude that A beta is synaptotoxic even in the absence of plaques and that high levels of A beta(1-42) are insufficient to induce plaque for mation in mice expressing wild-type hAPP. Our results support the emerging view that plaque-independent A beta toxicity plays an important role in the development of synaptic deficits in AD and related conditions.