Elucidating Pathogenic Mechanisms of Early-onset Alzheimer's Disease in Down Syndrome Patients

Jul 5, 2017Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan

Understanding the Causes of Early Alzheimer's Disease in People with Down Syndrome

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Abstract

The mean age of onset for familial Alzheimer's disease with a common mutation is about 55 years, despite early amyloid-β peptide overproduction in Down syndrome patients.

Down syndrome patients show Alzheimer's disease-like brain pathology by age 40-50 years.
Overexpression of the gene for amyloid precursor protein is thought to lead to increased amyloid-β production.
A poor correlation exists between average ages of Alzheimer's onset and the expected amyloid-β production.
Overexpression of DYRK1A in transgenic mice leads to Alzheimer's disease-like brain pathology.
DYRK1A overexpression suppresses the activity of neprilysin, a key enzyme that degrades amyloid-β in the brain.
Impaired neprilysin activity in Down syndrome patient-derived fibroblasts can be rescued by inhibiting DYRK1A.

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Down syndrome (DS) patients demonstrate the neuropathology of Alzheimer's disease (AD) characterized by the formation of senile plaques and neurofibrillary tangles by age 40-50 years. It has been considered for a number of years that 1.5-fold expression of the gene for the amyloid precursor protein (APP) located on chromosome 21 leading to overproduction of amyloid-β peptide (Aβ) results in the early onset of AD in adults with DS. However, the mean age of onset of familial AD with the Swedish mutation on APP which has high affinity for β-secretase associated with a dramatic increase in Aβ production is about 55 years. This paradox indicates that there is a poor correlation between average ages of AD onset and the theoretical amount of Aβ production and that there are factors exacerbating AD on chromosome 21. We therefore focused on dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), since overexpressing transgenic mice show AD-like brain pathology. The overexpression of DYRK1A caused suppression of the activity of neprilysin (NEP), which is a major Aβ-degrading enzyme in the brain, and phosphorylation at the NEP cytoplasmic domain. NEP activity was markedly reduced in fibroblasts derived from DS patients compared with that in fibroblasts derived from healthy controls. This impaired activity of NEP was rescued by DYRK1A inhibition. These results show that DYRK1A overexpression causes suppression of NEP activity through its phosphorylation in DS patients. Our results suggest that DYRK1A inhibitors could be effective against AD not only in adults with DS but also in sporadic AD patients.

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Elucidating Pathogenic Mechanisms of Early-onset Alzheimer's Disease in Down Syndrome Patients

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