Research Projects

Alzheimer’s disease (AD) is the most common cause of dementia and a leading cause of death, with significant morbidity and health care costs. By the time of diagnosis, there has already been significant and irreparable brain damage, and cognitive loss. Thus, screening and early diagnosis are key to effective and safe therapy. In this context, endosomal dysfunction, characterized by aberrant endosome size, number, and pH, have been recognized as the earliest and most prominent cellular pathologies observed decades before the onset of AD. Despite its importance, endosomal pathway has not been practically harnessed as a diagnostic or therapeutic tool in AD due to lack of identified druggable targets and critical gaps in our mechanistic understanding. Recent progress in this direction has been a new genetic study that discovered endosomal pH regulator NHE9 (gene SLC9A9) as a novel candidate locus for AD. Consistent with this, our preliminary data show marked downregulation of NHE9 expression in AD. Further, we also discovered endosomal pH alterations in skin fibroblasts from AD patients, which may reflect "inflammaging". The rationale for this study is to expand our knowledge of NHE9 in AD which may accelerate the identification of effective biomarkers and innovative therapies. The overarching goal of this study is to establish a collaborative research program aimed at examining the association of endosomal pH with AD. The objective of the research in this proposal is to develop mechanistic links between NHE9 function and endosomal pH with AD. The mechanistic hypothesis is that NHE9 downregulation causes luminal hyperacidification, disrupts endocytic recycling of amyloid precursor protein APP, altering the kinetics of amyloid beta production. This proposal will use a multidisciplinary approach, including iPSC derived models and advanced super resolution microscopy. There are three Aims. Aim 1 focuses on characterization of NHE9 in aging and AD using postmortem human brains, genetic variants, and cellular and clinical correlates. In Aim 2, we define molecular mechanisms governing the link between NHE9 and AD using (i) NHE9 loss-of-function patient iPSC derived models and (ii) human APOE isogenic-iPSC derived models. In Aim 3, we will screen for drugs that correct endosomal pH defect using a large compound library, and as well as develop endosomal pH alterations in skin fibroblasts as a potential early peripheral biomarker in AD. In summary, our research employs an integrated analytical and translational approach, leveraging on data acquired from large-scale ageing cohorts to inform our experimental studies. Our research group, along with collaborators, will bring together unique and complementary knowledge and expertise, putting us in an excellent position to examine the role of NHE9 in AD. Finally, we are developing human iPSC derived preclinical models for these studies, which we will share broadly and could be valuable to the scientific community.