Alzheimer's disease (AD) represents the most common age-related 
neurodegenerative disorder. It is characterized by the invariant accumulation of 
the beta-amyloid peptide (Abeta), which mediates synapse loss and cognitive 
impairment in AD. Current therapeutic approaches concentrate on reducing Abeta 
levels and amyloid plaque load via modifying or inhibiting the generation of 
Abeta. Based on in vivo two-photon imaging, we present evidence that side 
effects on the level of dendritic spines may counteract the beneficial potential 
of these approaches. Two potent gamma-secretase inhibitors (GSIs), DAPT 
(N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester) and 
LY450139 (hydroxylvaleryl monobenzocaprolactam), were found to reduce the 
density of dendritic spines in wild-type mice. In mice deficient for the amyloid 
precursor protein (APP), both GSIs had no effect on dendritic spine density, 
demonstrating that gamma-secretase inhibition decreases dendritic spine density 
via APP. Independent of the effects of gamma-secretase inhibition, we observed a 
twofold higher density of dendritic spines in the cerebral cortex of adult 
APP-deficient mice. This observation further supports the notion that APP is 
involved in the modulation of dendritic spine density--shown here for the first 
time in vivo.