Abstract
β-amyloid levels are elevated in Down syndrome (DS) patients throughout life and are believed to cause Alzheimer's disease (AD) in adult members of this population. However, it is not known if β-amyloid contributes to intellectual disability in younger individuals. We used a γ-secretase inhibitor to lower β-amyloid levels in young mice that model DS. This treatment corrected learning deficits characteristic of these mice, suggesting that β-amyloid-lowering therapies might improve cognitive function in young DS patients.
Highlights
Down syndrome (DS) is a complex genetic disorder that includes varying degrees of intellectual disability [1,2]
We provide evidence that cognitive deficits in DS can be corrected by controlling Ab production, itself a regulator of glutamatergic transmission
We propose that the cognitive improvement we observed in Ts65Dn mice treated with the c-secretase inhibitor, DAPT, resulted from lowered Ab levels [26,27,28]
Summary
Down syndrome (DS) is a complex genetic disorder that includes varying degrees of intellectual disability [1,2]. Occurring in approximately 1 in 700 births, DS results from trisomy of all or part of human chromosome 21 (trisomy 21) [3], which generally accounts for triplication of at least 100 genes. Among these is the gene encoding APP, as well as genes that upregulate APP expression [4]. Sequential cleavage of APP by b-secretase (BACE 1) and c-secretase produces peptides of varying lengths (mainly 40 and 42 amino acids), collectively termed b-amyloid, or Ab [5,6], which is widely believed to be an acute mediator of cognitive impairment [7], as well as a causative factor in Alzheimer’s disease (AD). Ab is over-produced in Down syndrome patients throughout life. Ab serum levels are 200% to 300% higher than in karyotypically normal individuals, and Ab accumulates within neurons and in amyloid plaques in juvenile and adult DS patients, respectively [8]
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