Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models

Autosomal dominant forms of familial Alzheimer's disease (FAD) are associat ed with increased production of the amyloid beta peptide, A beta 42, which is derived from the amyloid protein precursor (APP), In FAD, as Hell as in sporadic forms of the illness, A beta peptides accumulate abnormally. in th e brain in the form of amyloid plaques, Here, He show that overexpression o f FAD(717(V-->F))-mutant human APP in neurons of transgenic mice decreases the density of presynaptic terminals and neurons Hell before these mice dev elop amyloid plaques. Electrophysiological recordings from the hippocampus revealed prominent deficits in synaptic transmission, which also preceded a myloid deposition by several months. Although in young mice, functional and structural neuronal deficits Here of similar magnitude, functional deficit s became predominant with advancing age. Increased A beta production in the contest of decreased overall APP expression, achieved by addition of the S wedish FAD mutation to the APP transgene in a second line of mice, further increased synaptic transmission deficits in young APP mice without plaques. These results suggest a neurotoxic effect of A beta that is independent of plaque formation.