Lysosomal ion homeostasis as a novel biomarker for Alzheimer's disease. (20th December 2022) - Connolly, Owen
Abstract: Background: Protein clearance and neuronal homeostasis critically depend upon normal functioning of autophagy and endo‐lysosomal pathways ( Nixon, 2020; Usenovic & Krainc, 2012 ). Multiple studies show that lysosomal dysfunction is associated with Alzheimer's disease (AD), since impaired degradation of aggregate‐prone proteins can lead to pathological accumulations of Aβ plaques and neurofibrillary tau tangles ( Baranello et al., 2015; Rajendran & Annaert, 2012 ). To leverage this paradigm shift in our understanding of AD pathology, we have invented a pioneering, ion‐imaging technology using DNA nanodevices to non‐invasively map lysosomes for early AD detection. Method: Our lysosomal ion reporters are short DNA duplexes that simultaneously measure the concentrations of two ions ratiometrically, such as H + and Ca 2+ . We used dermal skin fibroblasts from a clinically diagnosed cohort of 120 samples comprising healthy individuals, AD, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson's and Huntington's disease patients. Using our lysosome mapping technology, we identified five distinct, AD‐related lysosomal features. A model probability score of predicting AD was calculated using a logistic binary regression. Result: Lysosomal ion profiles in age‐matched control groups showed significant differences compared to AD patients. Firstly, lysosomes from AD samples were found to be significantly more acidic and harbored more calcium than healthy samples. Secondly, resolving lysosomes into populations based on their pH and Ca 2+ levels revealed that two distinct lysosomal populations are significantly altered in AD. Our assay is 88% accurate (AUC: 0.91, 95% CI :0.84‐0.97) at identifying AD from other healthy and non‐AD related individuals with dementia. Further, we could detected AD‐related lysosomal dysfunction more than 19 years prior to symptom manifestation. Conclusion: Our novel ion‐mapping technology reports the ionic composition of single lysosomes of cultured cells. This enables early detection of AD in individuals who are either pre‐symptomatic, AD symptomatic, or suffer from other non‐AD dementia. This unique technology will allow us to build a drug discovery pipeline where we can specifically monitor the effect of pharmacological interventions and their impact on selective lysosomal populations, enabling personalized medicine for AD and other neurodegenerative diseases.