Abstract
BackgroundThe proteases (secretases) that cleave amyloid-β (Aβ) peptide from the amyloid precursor protein (APP) have been the focus of considerable investigation in the development of treatments for Alzheimer disease. The prediction has been that reducing Aβ production in the brain, even after the onset of clinical symptoms and the development of associated pathology, will facilitate the repair of damaged tissue and removal of amyloid lesions. However, no long-term studies using animal models of amyloid pathology have yet been performed to test this hypothesis.Methods and FindingsWe have generated a transgenic mouse model that genetically mimics the arrest of Aβ production expected from treatment with secretase inhibitors. These mice overexpress mutant APP from a vector that can be regulated by doxycycline. Under normal conditions, high-level expression of APP quickly induces fulminant amyloid pathology. We show that doxycycline administration inhibits transgenic APP expression by greater than 95% and reduces Aβ production to levels found in nontransgenic mice. Suppression of transgenic Aβ synthesis in this model abruptly halts the progression of amyloid pathology. However, formation and disaggregation of amyloid deposits appear to be in disequilibrium as the plaques require far longer to disperse than to assemble. Mice in which APP synthesis was suppressed for as long as 6 mo after the formation of Aβ deposits retain a considerable amyloid load, with little sign of active clearance.ConclusionThis study demonstrates that amyloid lesions in transgenic mice are highly stable structures in vivo that are slow to disaggregate. Our findings suggest that arresting Aβ production in patients with Alzheimer disease should halt the progression of pathology, but that early treatment may be imperative, as it appears that amyloid deposits, once formed, will require additional intervention to clear.
Highlights
Over a decade ago the amyloid cascade hypothesis predicted that increased levels of amyloid-b (Ab) peptide lead to secondary pathologies that culminate in the onset of Alzheimer disease (AD) [1]
We show that doxycycline administration inhibits transgenic amyloid precursor protein (APP) expression by greater than 95% and reduces Ab production to levels found in nontransgenic mice
This study demonstrates that amyloid lesions in transgenic mice are highly stable structures in vivo that are slow to disaggregate
Summary
Over a decade ago the amyloid cascade hypothesis predicted that increased levels of amyloid-b (Ab) peptide lead to secondary pathologies that culminate in the onset of Alzheimer disease (AD) [1]. New treatments are being developed that will decrease the amount of Ab produced from APP It is not clear whether lowering the production of Ab will allow the brain to heal itself by clearing the amyloid plaques. Turning off APP in these mice had the same effect as treating them with Ab-lowering drugs, and so the researchers were able to ask what happened to the amyloid plaques after Ab production was shut down. They showed that lowering Ab production prevents the amyloid lesions from getting worse as the disease progresses. The researchers found that the amyloid lesions that had formed before treatment was started remained intact throughout the experiment
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