Existing plaques and neuritic abnormalities in APP:PS1 mice are not affected by administration of the gamma-secretase inhibitor LY-411575

Abstract

The γ-secretase complex is a major therapeutic target for the prevention and treatment of Alzheimer's disease. Previous studies have shown that treatment of young APP mice with specific inhibitors of γ-secretase prevented formation of new plaques. It has not yet been shown directly whether existing plaques would be affected by γ-secretase inhibitor treatment. Similarly, alterations in neuronal morphology in the immediate vicinity of plaques represent a plaque-specific neurotoxic effect. Reversal of these alterations is an important endpoint of successful therapy whether or not a treatment affects plaque size. In the present study we used longitudinal imaging in vivo with multiphoton microscopy to study the effects of the orally active γ-secretase inhibitor LY-411575 in 10-11 month old APP:PS1 mice with established amyloid pathology and neuritic abnormalities. Neurons expressed YFP allowing fluorescent detection of morphology whereas plaques were labelled with methoxy-XO4. The same identified neurites and plaques were followed in weekly imaging sessions in living mice treated daily (5 mg/kg) for 3 weeks with the compound. Although LY-411575 reduced Aβ levels in plasma and brain, it did not have an effect on the size of existing plaques. There was also no effect on the abnormal neuritic curvature near plaques, or the dystrophies in very close proximity to senile plaques. Our results suggest that therapeutics aimed at inhibition of Aβ generation are less effective for reversal of existing plaques than for prevention of new plaque formation and have no effect on the plaque-mediated neuritic abnormalities, at least under these conditions where Aβ production is suppressed but not completely blocked. Therefore, a combination therapy of Aβ suppression with agents that increase clearance of amyloid and/or prevent neurotoxicity might be needed for a more effective treatment in patients with pre-existing pathology.

Four-dimensional microglia response to anti-Aβ treatment in APP/PS1xCX3CR1/GFP mice

“…Further analysis showed a significant reduction of senile plaque size using two-way ANOVA for repeated samples followed by Tamhane test [F (15,491) = 3.906; *p < 0.001, vs. day 1]. No significant differences were observed in untreated mice along the imaging sessions (two-way ANOVA treatment×day effect: [F (7,137) = 0.593; p = 867]) as previously described, 19,26,27 supporting the fact that senile plaques do not change in size at these time intervals once deposited (Fig. 1).…”

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“…This is also illustrated by a study investigating effectiveness of thesecretase inhibitor LY-411575 in older (10-11 months) APP/PS1 transgenic mice [143]. In these mice, treatment decreased the formation of A , but it did not clear the preexisting amyloid plaques, neither did it reverse the associated neuritic abnormalities.…”

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“…Based on this knowledge, novel treatments aimed at inhibiting Aβ toxicity have been developed and are now being tested on patients. These new types of drugs are likely to be the most effective if initiated in pre-dementia stages of AD before neuronal degeneration has become too widespread and severe, a view supported by the results of treatment studies in mice [9,10,11]. However, clinical methods to recognize incipient AD are lacking.…”