γ-Secretase Inhibition Reduces Spine DensityIn Vivovia an Amyloid Precursor Protein-Dependent Pathway

Abstract

Alzheimer's disease (AD) represents the most common age-related neurodegenerative disorder. It is characterized by the invariant accumulation of the ␤-amyloid peptide (A␤), which mediates synapse loss and cognitive impairment in AD. Current therapeutic approaches concentrate on reducing A␤ levels and amyloid plaque load via modifying or inhibiting the generation of A␤. 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 ␥-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 ␥-secretase inhibition decreases dendritic spine density via APP. Independent of the effects of ␥-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.

Controlled Cortical Impact Results in an Extensive Loss of Dendritic Spines that Is Not Mediated by Injury-Induced Amyloid-Beta Accumulation

“…26 Conversely, a 4-day administration of c-secretase inhibitors DAPT and LY450139 has been found to reduce spine numbers in mice through an APP dependent pathway. 27 Here we found that c-secretase inhibition did not alter spine loss after TBI, and thus it does not appear that c-secretase plays a pivotal role in dendritic spine loss after injury. It is interesting to note, however, that the amount of dendritic spine loss caused by TBI was considerably smaller in the LY450139 study than in our initial experiments.…”

Genetic Analysis Reveals that Amyloid Precursor Protein and Death Receptor 6 Function in the Same Pathway to Control Axonal Pruning Independent of β-Secretase

“…Coincident loss-of-function phenotypes have also been observed for dendritic spines in cortical layers 2/3, because loss of either APP or DR6 causes an increase in spine density that is dose dependent for both genes (i.e., loss of one APP or DR6 allele gives a partial phenotype that is increased further when the second allele of the gene is lost; Bittner et al, 2009;Kallop et al, 2014); furthermore, loss of both APP and DR6 (in APP;DR6 double-knock-out mouse) does not increase spine density beyond what is observed in either single mutant alone (Kallop et al, 2014)-a nonadditivity of effects that is again consistent with APP and DR6 functioning in the same pathway.…”

“…We confirmed that AZ29 protected axons from degeneration after NGF deprivation in wild-type sensory neurons, as described previously (Nikolaev et al, 2009), but observed a similar protective effect of AZ29 on sensory axons from Bace-1;Bace-2 double KO mice (mean degeneration index in the presence of AZ29: wild-type axons, 0.73 Ϯ 0.4; Bace-1;Bace-2 KO axons, 0.76 Ϯ 0.5; p Ͼ 0.1, n ϭ 5 experiments). Therefore, AZ29 produces its effect in an off-target manner, which is surprising given the dose dependence of its protective effect and its reported specificity and given that protection by small-molecule inhibitors is not commonly observed in this assay (Chen et al, 2012). Collectively, these results also indicate that BACE-1 (and BACE-2) is not required for degeneration of sensory axons in response to trophic factor deprivation, which is consistent with the fact that Bace-1 is not required for RGC pruning in vivo.…”

APP physiological and pathophysiological functions: insights from animal models

“…Also, attempts to examine dendritic spine density in APP KO mice have revealed mixed results. Bittner et al [46] reported that APP deletion leads to a twofold higher density of spines in apical dendrites of layer III and layer V neurons of the somatosensory cortex at 4-6 months of age, whereas Lee et al [47] found a significant decrease in spine density in cortical layers II/III and hippocampal CA1 pyramidal neurons in 1-year-old APP KO mice compared with wildtype controls. This discrepancy may be due to a regionspecific effect, a contribution of aging and/or an adaptive mechanism.…”