Integrated Multimodal *Omics of Neuropeptide Proteoforms to Assess their Suitability as Biomarkers and Therapeutic Targets for Alzheimer’s Disease
Alzheimer’s Disease (AD) is a complicated disease with no effective treatment yet available. AD is currently defined by the abundance of two insoluble proteins, amyloid-b and tau, but the amount of these proteins does not accurately predict cognitive problems in people with AD. Recent studies have found that neuropeptides, a group of secreted proteins that can be cut down into many different, shorter peptides, are widely dysregulated in AD, and might play roles in the AD disease process. In this proposal we investigate whether neuropeptides may be used to more accurately assess AD patients, and whether supplementation with these peptides might eventually prove a new potential therapy for AD.
The goal of this project is to explore the structure and function of a small number of neuropeptide proteins that have been highlighted as being consistently dysregulated in Alzheimer's Disease by protein screens. Neuropeptides are proteins that are synthesized in neurons in the brain as long protein strands, before being cleaved by enzymes into shorter peptides that have diverse functions in the brain. Using advanced liquid chromatography mass-spectrometry proteomic techniques, we will comprehensively map the peptides produced by four key neuropeptide proteins (Neurosecretory Protein VGF, Secretogranins 2 & 3, and Chromogranin A), and build a highly reproducible method to accurately quantify these peptides. This method will be used to measure peptide levels in cerebrospinal fluid, brain tissue, and stem cells donated by people with Alzheimer’s Disease and carefully matched controls. Finally, the peptides that are most dysregulated in each matrix will be used to treat stem cells, to characterize the signaling changes induced by the peptide. In completing this project we hope to gain a better understanding of the structure of neuropeptides, of the enzymes that regulate them, and how they may interact to alter an individual’s susceptibility to Alzheimer’s Disease. This may lead to better biomarkers of synapse function, the strongest correlate for cognitive decline in Alzheimer’s Disease, and may highlight protective mechanisms of neuropeptides that can be targeted for future novel treatments.
About the Researcher
Dr. Carlyle began her training as an Undergraduate at the University of Oxford, where she gained a First Class degree in Medical Sciences in 2005. Rather than continue to complete her medical training, she felt the pull of molecules and sample tubes, and transitioned to complete a Ph.D. at the University of Edinburgh, where she studied the downstream signaling interactions of a schizophrenia risk gene, DISC1. Upon completion of her Ph.D. in 2010, she moved to the USA, where she was trained in proteomic and transcriptomic analysis of brain tissue in the labs of Dr. Arthur Simen and Professor Angus Nairn. In 2017 she was recruited to the Alzheimer’s Clinical and Translational Research Unit (ACTRU) at Massachusetts General Hospital / Harvard Medical School by Professor Steven Arnold. She is currently an Instructor in Neurology, leading biomarker discovery projects and proteomics informed mechanistic studies with the ultimate goal of developing more informative biomarkers for Alzheimer’s Disease that can be used in novel Clinical Trials.
The pace of technological advancement in the field of proteomics and transcriptomics over the course of my career has been truly astonishing. We have gone from being able to accurately quantify a handful of proteins in a single experiment to being able to quantify thousands. Over the same time period, clinical trial after trial has failed in Alzheimer’s Disease, leaving millions of families without hope for a cure in their lifetimes. Proteomic and transcriptomic techniques enable us to take a step back from the long-held view that Alzheimer’s is a disease of two proteins, and allows us to measure whole protein networks and understand the wide scale dysregulation seen in this disease on a global level. I am driven by the likelihood that these approaches will highlight new targets for treatment, give us better predictive markers of disease progression, accelerate the pace of discovering novel therapies, and help identify groups of people that may respond to personalized medicine. By working closely with clinicians in a research unit like ACTRU, I hope to contribute significantly to this larger goal. I am extremely grateful for the support of my project from BrightFocus donors, which will contribute directly to progress in the biomarker field, and may offer routes for novel therapeutics.
First published on: July 2, 2019
Last modified on: August 27, 2019