期刊
MOLECULAR PSYCHIATRY
卷 21, 期 10, 页码 1333-1341出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/mp.2016.134
关键词
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资金
- FRAXA Research Foundation
- NIH [R21AG044714, R03HD075881, R01AG051086, R21AG4687100, P30AG010133]
- University of Wisconsin (UW)-Madison Alzheimer's Disease Research Center (NIA) [P50AG033514]
- UW-Madison Clinical and Translational Science Award (CTSA) program [NCATS UL1TR000427]
- Lundbeck USA
- Merz Pharmaceuticals
- Pierre Fabre
- Riley Memorial Foundation
- Mental Health Association for the Advancement of Mental Health Research and Education
- Clarian Health Partners
- Indiana University Collaborative Research Grant [22-140-29]
- Alzheimer's Association
- Indiana Clinical and Translational Sciences Institute (ICTSI)
- ISDH Spinal Cord and Brain Injury Board
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and is associated with up to 5% of autism cases. Several promising drugs are in preclinical testing for FXS; however, bench-to-bedside plans for the clinic are severely limited due to lack of validated biomarkers and outcome measures. Published work from our laboratories has demonstrated altered levels of amyloid-beta (A beta) precursor protein (APP) and its metabolites in FXS and idiopathic autism. Westmark and colleagues have focused on beta-secretase (amyloidogenic) processing and the accumulation of A beta peptides in adult FXS models, whereas Lahiri and Sokol have studied a-secretase (non-amyloidogenic or anabolic) processing and altered levels of sAPP alpha and A beta in pediatric autism and FXS. Thus, our groups have hypothesized a pivotal role for these Alzheimer's disease (AD)-related proteins in the neurodevelopmental disorders of FXS and autism. In this review, we discuss the contribution of APP metabolites to FXS and autism pathogenesis as well as the potential use of these metabolites as blood-based biomarkers and therapeutic targets. Our future focus is to identify key underlying mechanisms through which APP metabolites contribute to FXS and autism condition-to-disease pathology. Positive outcomes will support utilizing APP metabolites as blood-based biomarkers in clinical trials as well as testing drugs that modulate APP processing as potential disease therapeutics. Our studies to understand the role of APP metabolites in developmental conditions such as FXS and autism are a quantum leap for the neuroscience field, which has traditionally restricted any role of APP to AD and aging.
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