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

Autosomal dominant forms of familial Alzheimer's disease (FAD) are associated 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 the brain in the form of amyloid plaques, Here, He show that overexpression of FAD(717(V-->F))-mutant human APP in neurons of transgenic mice decreases the density of presynaptic terminals and neurons Hell before these mice develop amyloid plaques. Electrophysiological recordings from the hippocampus revealed prominent deficits in synaptic transmission, which also preceded amyloid deposition by several months. Although in young mice, functional and structural neuronal deficits Here of similar magnitude, functional deficits became predominant with advancing age. Increased A beta production in the contest of decreased overall APP expression, achieved by addition of the Swedish 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.