期刊
JOURNAL OF ALZHEIMERS DISEASE
卷 73, 期 4, 页码 1541-1554出版社
IOS PRESS
DOI: 10.3233/JAD-190442
关键词
Alzheimer's disease; amyloid-beta; BPN-15606; cognitive deficits; gamma-secretase modulator; preventative therapy; PSAPP
资金
- National Institute of Neurologic Disorders and Stroke/National Institute of Aging [U01-NS074501, U01AG048986]
- Cure Alzheimer's Fund
Background: In the amyloid hypothesis of Alzheimer's disease (AD), the dysregulation of amyloid-beta protein (A beta) production and clearance leads to amyloid deposits, tau tangles, neuronal loss, and cognitive dysfunction. Thus far, therapies targeting the enzymes responsible for A beta production have been found ineffective or having significant side effects. Objective: To test whether a gamma-secretase modulator, BPN-15606, is an effective disease-modifying or preventative treatment in the PSAPP mouse model of AD. Methods: We treated pre-plaque (3-month-old) and post-plaque (6-month-old) PSAPP AD transgenic mice for 3 months and examined behavioral, biochemical, and pathological end points. Results: BPN-15606 attenuated cognitive impairment and reduced amyloid plaque load, microgliosis, and astrogliosis associated with the AD phenotype of PSAPP mice when administered to pre-plaque (3-month-old) but was ineffective when administered to post-plaque (6-month-old) mice. No treatment-related toxicity was observed. Conclusion: BPN-15606 appears efficacious when administered prior to significant pathology.
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