Drosophila Eye Model to Study Neuroprotective Role of CREB Binding Protein (CBP) in Alzheimer's Disease.

Timothy Cutler,Ankita Sarkar,Neha Gogia,Michael Moran,Meghana Tare,Greg Mancini,Oorvashi Roy Puli,Andrew Steffensmeier,Amit Singh,Udai Pandey

doi:10.1371/journal.pone.0137691

Abstract

BackgroundThe progressive neurodegenerative disorder Alzheimer’s disease (AD) manifests as loss of cognitive functions, and finally leads to death of the affected individual. AD may result from accumulation of amyloid plaques. These amyloid plaques comprising of amyloid-beta 42 (Aβ42) polypeptides results from the improper cleavage of amyloid precursor protein (APP) in the brain. The Aβ42 plaques have been shown to disrupt the normal cellular processes and thereby trigger abnormal signaling which results in the death of neurons. However, the molecular-genetic mechanism(s) responsible for Aβ42 mediated neurodegeneration is yet to be fully understood.Methodology/Principal FindingsWe have utilized Gal4/UAS system to develop a transgenic fruit fly model for Aβ42 mediated neurodegeneration. Targeted misexpression of human Aβ42 in the differentiating photoreceptor neurons of the developing eye of transgenic fly triggers neurodegeneration. This progressive neurodegenerative phenotype resembles Alzheimer’s like neuropathology. We identified a histone acetylase, CREB Binding Protein (CBP), as a genetic modifier of Aβ42 mediated neurodegeneration. Targeted misexpression of CBP along with Aβ42 in the differentiating retina can significantly rescue neurodegeneration. We found that gain-of-function of CBP rescues Aβ42 mediated neurodegeneration by blocking cell death. Misexpression of Aβ42 affects the targeting of axons from retina to the brain but misexpression of full length CBP along with Aβ42 can restore this defect. The CBP protein has multiple domains and is known to interact with many different proteins. Our structure function analysis using truncated constructs lacking one or more domains of CBP protein, in transgenic flies revealed that Bromo, HAT and polyglutamine (BHQ) domains together are required for the neuroprotective function of CBP. This BHQ domain of CBP has not been attributed to promote survival in any other neurodegenerative disorders.Conclusions/SignificanceWe have identified CBP as a genetic modifier of Aβ42 mediated neurodegeneration. Furthermore, we have identified BHQ domain of CBP is responsible for its neuroprotective function. These studies may have significant bearing on our understanding of genetic basis of AD.

Highlights

Alzheimer’s disease (AD; OMIM: 104300) is an age related progressive neurodegenerative disease
The Aβ42 polypeptides are generated by improper cleavage of the Amyloid-Precursor Protein (APP) by β- and γ- secretase, which results in a forty-two amino-acid long polypeptide, and referred to as amyloid-beta 42 (Aβ42) [4, 6, 12,13,14,15]
We have shown that the misexpression of human Aß42 in the retina (GMR Gal4 > UAS Aß42) shows a stronger phenotype when maintained at 29°C with no penetrance [10]

Summary

Introduction

Alzheimer’s disease (AD; OMIM: 104300) is an age related progressive neurodegenerative disease. The Aβ42 polypeptides are generated by improper cleavage of the Amyloid-Precursor Protein (APP) by β (a membrane bound aspartyl protease called BACE)- and γ- secretase, which results in a forty-two amino-acid long polypeptide, and referred to as amyloid-beta 42 (Aβ42) [4, 6, 12,13,14,15]. Accumulation of Aβ42 plaques are coincident with the abrupt signaling in the neuronal cell [10, 16] It results in the disruption of major cellular processes and is manifested as oxidative stress, ER stress, generation of reactive oxygen species (ROS), trigger inflammatory processes [8]. It results in triggering cell death in the neurons. The molecular-genetic mechanism(s) responsible for Aβ42 mediated neurodegeneration is yet to be fully understood

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Conclusion