Gamma-secretase inhibition reduces spine density in vivo via an amyloid precursor protein-dependent pathway
J Neurosci. 2009 Aug 19;29(33):10405-9.
|Type of Publication:
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.