Amantha Thathiah, Ph.D

A brief summary of Dr. Thathiah’s work in 2017 and a preview of what’s to come in 2018

Alzheimer’s disease is the most common type of dementia in people aged 65 or older and is one of the biggest medical and social challenges of our generation. Of the top ten leading causes of death worldwide, Alzheimer’s disease is the only one that we cannot prevent, cure, or slow down its progress. Several FDA-approved drugs can ameliorate some of the symptoms of Alzheimer’s disease, but no current intervention strategies can halt or modify the underlying disease mechanisms.

Alzheimer’s disease is clinically characterized by progressive brain cell loss and inflammation, memory impairment, cognitive deficits, and behavioral changes. Postmortem studies of the brains from patients reveal two pathological hallmarks of the disease: (1) amyloid plaques, composed of aggregates of the amyloid-beta protein, and (2) neurofibrillary tangles, composed of aggregates of the tau protein. An imbalance between the production and clearance of amyloid-beta initiates a cascade of events, progressively leading to tau pathology, inflammation, brain cell loss, and, consequently, memory loss. A major challenge for the future is to gain a clearer understanding of disease mechanisms in order to develop effective therapeutic strategies.

G protein-coupled receptors (GPCRs) are the largest family of membrane proteins and the most common target for therapeutic drugs. As such, the discovery that GPCRs regulate amyloid-beta production has offered fresh hope for Alzheimer’s disease drug discovery. We determined that genetic deletion or removal of a GPCR called GPR3 reduces the amyloid plaque burden and alleviates the cognitive deficits in mouse models of Alzheimer’s disease. These studies indicate that GPR3 is involved in Alzheimer’s disease progression and provide significant validation for GPR3 as a therapeutic target for Alzheimer’s disease. In collaboration with the Clear Thoughts Foundation, we aimed to determine the full repertoire of aberrantly expressed GPCRs in Alzheimer’s disease patient brain samples and to investigate whether the identified GPCRs are involved in Alzheimer’s disease pathogenesis. To explore putative changes in the expression profile of GPCRs in the Alzheimer’s disease brain, we first obtained human brain tissue samples from control subjects and Alzheimer’s disease patients from two brain banks. We then performed direct ultra‐high‐throughput sequencing of the DNA from each brain sample to determine the express profile of GPCRs in health and disease in the human brain. Following analysis of the huge set of data, we have exciting data to indicate that several unique GPCRs are aberrantly expressed in the Alzheimer’s disease brain samples in comparison to control subjects. To validate the DNA sequencing results, we used a technique called quantitative real‐time polymerase chain reaction (qPCR) for its high sensitivity, specificity and broad dynamic range to validate the changes in GPCR expression. We have now begun to investigate the functional relevance of changes in GPCR expression on amyloid-beta pathology in vitro in human brain cell lines. We now have compelling preliminary evidence to indicate that at least one of the identified is involved modulation of amyloid-beta levels. Upon completion of these in vitro studies, we aim to then investigate the function of the identified GPCR(s) in vivo in Alzheimer’s disease mouse models. Collectively, we anticipate that these studies will lead to the identification of novel GPCRs involved in the pathophysiology of Alzheimer’s disease and identify putative novel therapeutic targets for Alzheimer’s disease.