One major hallmark of Alzheimer's disease (AD) is the massive loss of synapses 
that occurs at an early clinical stage of the disease. In this study, we 
characterize alterations in spine density and the expression of 
synapse-associated immediate early gene Arc (activity-regulated 
cytoskeleton-associated protein) in the hippocampal CA1 regions of two different 
amyloid precursor protein (APP) transgenic mouse lines before plaque development 
and their connection to performance in hippocampus-dependent memory tests. The 
density of mushroom-type spines was reduced by 34% in the basal dendrites 
proximal to the soma of CA1 pyramidal neurons in 5.5-month-old Tg2576 mice, 
carrying the Swedish mutation, compared with wild-type littermates. A similar 
reduction of 42% was confirmed in the same region of 8-month-old APP/Lo mice, 
carrying the London mutation. In this strain, the reduction extended to the 
distal dendritic spines (28%), although no differences were found in apical 
dendrites in either transgenic mouse line. Both transgenic mice lines presented 
a significant increase in Arc protein expression in CA1 compared with controls, 
suggesting rather an overactivity and increased spine turnover that was 
supported by a significant decrease in number of somatostatin-immunopositive 
inhibitory interneurons in the stratum oriens of CA1. Behaviorally, the 
transgenic mice showed decrease freezing in the fear contextual conditioning 
test and impairment in spatial memory assessed by Morris water maze test. These 
data indicate that cognitive impairment in APP transgenic mice is correlated 
with impairment of synaptic connectivity in hippocampal CA1, probably 
attributable to loss of inhibitory interneurons and subsequent hyperactivity.