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O5‐06‐01: TDP‐43 Suppresses TAU Expression VIA Promoting its Mrna Instability
Author(s) -
Liu Fei,
Gu Jianlan,
Jin Nana,
Zhang Yanchong,
Chu Dandan,
Qian Wei,
Gong Cheng-Xin,
Iqbal Khalid
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.735
Subject(s) - neurodegeneration , messenger rna , frontotemporal lobar degeneration , tau protein , untranslated region , tauopathy , biology , microbiology and biotechnology , pathology , alzheimer's disease , medicine , frontotemporal dementia , gene , genetics , disease , dementia
heimer’s disease (AD) could facilitate screening and enrollment of better defined participants into clinical trials, and enable disease progression and treatment response monitoring. Neurodegenerative diseases (NDs), including AD, Parkinson’s disease (PD), and frontotemporal degeneration (FTD), may begin with a prolonged asymptomatic stage. Further, many NDs can present with similar clinical manifestations at early stages. While early stages of NDs affect different brain regions, most NDs are characterized by early synapse dysfunction/loss. We have developed a novel approach for early detection and monitoring of neurodegeneration based on targeted selection and quantitative analysis of microRNA (miRNA) biomarkers enriched in certain brain regions, present in synapses, and detectable in plasma. Effective miRNA biomarker “pairs” are comprised of one miRNA enriched in synapses of brain regions affected by disease (e.g. hippocampus for AD) and a miRNA enriched in different brain regions. Methods: RNA was extracted from patient and control plasma samples. Plasma concentrations of miRNAs were analyzed by individual RT-qPCR and statistical analysis of miRNA ratios was performed using customized software, essentially as described in Sheinerman et al. Aging 2013.Results:Recent, unpublished data will be presented. In collaboration with Washington University, plasma samples from 30 cognitively normal (CDR 0) amyloid negative subjects and 29 amyloid positive subjects with very mild/mild dementia, CDR 0.5-1, were analyzed and differentiated with 86% accuracy. In the second study, 84 plasma samples from donors cognitively normal at enrollment were analyzed. 42 subjects later have progressed to CDR>0 (“progressors”), and 42 have remained cognitively normal during 3-12 years observation period (“non-progressors”). miRNA biomarkers differentiated “progressors” from “non-progressors” with 78% accuracy, and amyloid positive and negative “progressors” with 79% accuracy. In the cohort recruited at University of Pennsylvania, levels of miRNAs were measured in plasma of 250 subjects with AD, PD, FTD, amyotrophic lateral sclerosis (ALS), and controls. miRNA pairs capable of effectively differentiating each ND from control with >90% accuracy and from each other with 87%-98% accuracy have been established. Conclusions: These data strongly support applicability of the proposed approach to early detection and differential diagnosis of AD. Larger, longitudinal studies are ongoing.