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.
Highlights
Alzheimer's disease (AD) is the most common cause of dementia among elderly people and it has no known cure
Senile plaques are associated with neuritic dystrophies and synaptic loss [4,5,6] and it has been shown that senile plaques may disrupt cortical synaptic integration[7]
Will inhibition of γ-secretase lead to the clearance of existing plaques or the reversal of the morphological alterations in neurons in the mouse models of AD? In the present work, we use a well characterized γsecretase inhibitor, N(2)-[(2S)-2-(3,5-difluorophenyl)-2hydroxyethanoyl]-N(1)-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-l-alaninamide (LY411575) [21,22] and multiphoton microscopy to assess in vivo the effect of long-term treatment on existing senile plaques and the neuronal abnormalities associated with the plaques in APPswe/PS1dE9 mice
Summary
Alzheimer's disease (AD) is the most common cause of dementia among elderly people and it has no known cure. There has been considerable success in generating small molecules capable of entering the central nervous system that inhibit γ-secretase activity potently leading to a sustained reduction in brain Aβ levels [12] In both humans and animal models, the use of γsecretase inhibitors to reduce Aβ levels and slow Aβ deposition has been demonstrated. We use a well characterized γsecretase inhibitor, N(2)-[(2S)-2-(3,5-difluorophenyl)-2hydroxyethanoyl]-N(1)-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-l-alaninamide (LY411575) [21,22] and multiphoton microscopy to assess in vivo the effect of long-term treatment on existing senile plaques and the neuronal abnormalities associated with the plaques in APPswe/PS1dE9 mice This animal model shows early deposition of Aβ by 4–6 months of age [23,24] and develops neuritic dystrophies and abnormal neuritic curvature [5,25]. At the age used in this study (10–11 months old) the Aβ deposition and related neuropathological changes represent a model of established neuropathology
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