Bidirectional Regulation of Amyloid Precursor Protein-Induced Memory Defects by Nebula/DSCR1: A Protein Upregulated in Alzheimer's Disease and Down Syndrome.

Abstract

Aging individuals with Down syndrome (DS) have an increased risk of developing Alzheimer's disease (AD), a neurodegenerative disorder characterized by impaired memory. Memory problems in both DS and AD individuals usually develop slowly and progressively get worse with age, but the cause of this age-dependent memory impairment is not well understood. This study examines the functional interactions between Down syndrome critical region 1 (DSCR1) and amyloid-precursor protein (APP), proteins upregulated in both DS and AD, in regulating memory. Using Drosophila as a model, we find that overexpression of nebula (fly homolog of DSCR1) initially protects against APP-induced memory defects by correcting calcineurin and cAMP signaling pathways but accelerates the rate of memory loss and exacerbates mitochondrial dysfunction in older animals. We report that transient upregulation of Nebula/DSCR1 or acute pharmacological inhibition of calcineurin in aged flies protected against APP-induced memory loss. Our data suggest that calcineurin dyshomeostasis underlies age-dependent memory impairments and further imply that chronic Nebula/DSCR1 upregulation may contribute to age-dependent memory impairments in AD in DS.

SIGNIFICANCE STATEMENT:

Most Down syndrome (DS) individuals eventually develop Alzheimer's disease (AD)-like dementia, but mechanisms underlying this age-dependent memory impairment remain poorly understood. This study examines Nebula/Down syndrome critical region 1 (DSCR1) and amyloid-precursor protein (APP), proteins upregulated in both DS and AD, in regulating memory. We uncover a previously unidentified role for Nebula/DSCR1 in modulating APP-induced memory defects during aging. We show that upregulation of Nebula/DSCR1, an inhibitor of calcineurin, rescues APP-induced memory defects in young flies but enhances memory loss of older flies. Excitingly, transient Nebula/DSCR1 overexpression or calcineurin inhibition in aged flies ameliorates APP-mediated memory problems. These results suggest that chronic Nebula/DSCR1 upregulation may contribute to age-dependent memory loss in DS and AD and points to correcting calcineurin signaling as a means to improve memory during aging.

• Authors: Jillian L Shaw, Shixing Zhang, Karen T Chang
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 35 Issue 32 Pg. 11374-83 (Aug 12 2015) ISSN: 1529-2401 [Electronic] United States
• PMID: 26269644 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 the authors 0270-6474/15/3511374-10$15.00/0.

Chemical References

• Amyloid beta-Protein Precursor
• Calcium-Binding Proteins
• Drosophila Proteins
• Intracellular Signaling Peptides and Proteins
• Sra protein, Drosophila
• Cyclic AMP-Dependent Protein Kinases
• Calcineurin

Topics

• Alzheimer Disease (metabolism)
• Amyloid beta-Protein Precursor
• Animals
• Calcineurin (metabolism)
• Calcium-Binding Proteins
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Down Syndrome (metabolism)
• Drosophila Proteins (genetics, metabolism)
• Drosophila melanogaster
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Memory Disorders (chemically induced, genetics, metabolism)
• Up-Regulation