Rare and Common Variation Implicate Microglial Function in AD Risk

by Alison Goate

• Willard T.C. Johnson Research Professor of Neurogenetics, Professor of Neuroscience, Professor of Neurology, Professor of Genetics & Genomic Sciences, ISMMS, New York
• Director, Ronald Loeb Center for Alzheimer’s Disease
• Associate Director, Alzheimer’s Disease Research Center

Biography

The focus of my research is the genetics of neuropsychiatric disorders. My lab has contributed to the study of Alzheimer’s disease (AD) and related dementias and addiction, including alcohol and nicotine dependence.
I have contributed to the identification of all genes implicated in AD risk and most of those implicated in frontotemporal dementia (FTD). We were the first to report mutations in amyloid precursor protein as a cause of AD. This was the first cause of AD to be identified and has led to the development of anti-amyloid therapies including vaccines, gamma-secretase inhibitors and beta-secretase inhibitors. My lab was also first to identify mutations in microtubule associate protein tau as a cause of FTD. Several anti-tau therapeutics are now being developed for tauopathies.
More recently my laboratory was part of the team that first identified rare variants in TREM2 as a risk factor for AD and led the team that identified rare variants in PLD3 as a risk factor for AD. We have also demonstrated that AD risk genes are highly enriched for microglial expressed gnes, particularly those regulated by SPI1/PU.1.
We are currently using OMICs approaches to identify novel risk and protective factors for AD and developing animal and cell models to study the molecular effects of these variants.  Our studies of nicotine dependence led to the identification of the most replicable risk factor in psychiatric genetics: A common missense allele in CHRNA5. We have also demonstrated that rare and low frequency variants in other neuronal nicotinic receptors and in alcohol and nicotine metabolism genes that influence risk for nicotine and alcohol dependence across populations.
We are currently using genomic approaches in the COGA dataset to identify variants associated with alcohol dependence and related traits.

Recommended reading

• Sims et al. 2017, Nat Genetics – Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease
• Huang et al. 2017, Nat Neurosci – A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease
• Pimenova et al. 2017, Immunity – A Tale of Two Genes: Microglial Apoe and Trem2

Swiss Federal Institute of Technology, Lausanne

A shared goal of neuroscience and robotics is to understand how systems can be built to move effectively through the world. However, state-of-the-art algorithms for selecting and executing limbed behaviors in robots are still quite primitive compared with those used by animals. To inform robotic control approaches, we are investigating how the fly, Drosophila melanogaster, controls complex movements. I will discuss how we are combining 2-photon imaging of the ventral nerve cord in behaving Drosophila with physics-based simulations and neural network modeling to uncover how flies achieve flexible behaviours.

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The overarching goal of my research program is to understand how neural connections are formed, remodeled, and maintained in the brain and to transform this knowledge into a better understanding of learning/memory processes and brain disorders/diseases. More precisely, my research focuses on: (1) Understanding neuron-glial communication during brain development and its relationship to neurodevelopmental disorders including Fragile X and Down syndrome, and intellectual disability, and (2) Discovering mechanisms regulating synaptic plasticity and memory formation in the healthy and diseased brain. We are actively working to translate our basic discoveries into effective treatments for developmental brain disorders and neurodegenerative diseases.

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