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Impact of neuronal exosomes-delivered microRNA and proteins on the pathogenesis of Alzheimer's disease

Final Report Summary - EMIRAD (Impact of neuronal exosomes-delivered microRNA and proteins on the pathogenesis of Alzheimer's disease)

Alzheimer’s disease (AD) is an age-related neurodegenerative disease characterized by synapse loss, extracellular amyloid plaques formed by amyloid-β peptide (Aβ) and intracellular aggregates of both Aβ and hyper-phosphorylated Tau protein. While genetic evidence highlights a causative role for mutations in APP, PSEN1 and PSEN2 genes for early-onset AD, the causes of sporadic late-onset AD are still unknown. There is increasing evidence that a deregulation of the expression of microRNAs (miRNAs) is at the basis of many human diseases, comprising neurodegenerative diseases. Moreover, the quantification of deregulated miRNA expression using biofluids (blood, cerebrospinal fluid,…) is increasingly used as a novel way to diagnose diseases and to monitor disease progression.
In order to understand if a deregulation of miRNA expression levels can be used to help in the diagnosis of AD, we have profiled miRNAs isolated from samples of cerebrospinal fluid (CSF) withdrawn ante-mortem from AD patients and age-matched healthy control subjects (1). We found that the levels of miR-27a-3p were significantly reduced in the AD cohort, and we confirmed the finding in a second cohort of subjects. Moreover, we demonstrated that expression levels of miRNAs in post-mortem and ante-mortem CSF are not correlated, highlighting the importance of studying ante-mortem CSF for biomarker discovery. In an effort to further understand the functional roles of miR-27a-3p and how its de-regulation could participate to AD pathology, we have shown that mRNAs encoding for AD-relevant proteins (BACE1, GSK3beta, MAPT and PSEN1) are indeed targets of miR-27a-3p.
In order to understand if miRNAs are deregulated in AD brain, we have profiled miRNAs in prefrontal cortex and hippocampus of AD and healthy control subjects using nanostring molecular counting and deep-sequencing, followed by quantitative PCR validation. One miRNA, miR-132-3p, was consistently found down-regulated in AD (2). By in situ hybridization and immunostaining we showed that neurons with lower expression of miR-132-3p had also higher levels of phosphorylated Tau. Luciferase assays identified FOXO1a as a miR-132-3p target and subsequent western blotting of human brain samples confirmed an increase of FOXO1a expression in AD samples.
Our studies have contributed to elucidate the roles of miRNAs in AD pathology. We have discovered that measurement of the expression levels of miR-27a in CSF is helpful in differentiating between AD and CT. We have also highlighted that miR-132-3p is down regulated in AD and that it could participate to establish AD pathology by altering FOXO1a levels.

(1) Sala Frigerio C, Lau P, Salta E, Tournoy J, Bossers K, Vandenberghe R, Wallin A, Bjerke M, Zetterberg H, Blennow K, De Strooper B. Reduced expression of hsa-miR-27a-3p in CSF of patients with Alzheimer disease. Neurology. 2013 Dec 10;81(24):2103-6. PMID: 24212398
(2) Lau P, Bossers K, Janky R, Salta E, Sala Frigerio C, Barbash S, Rothman R, Sierksma AS, Thathiah A, Greenberg D, Papadopoulou AS, Achsel T, Ayoubi T, Soreq H, Verhaagen J, Swaab DF, Aerts S, De Strooper B. Alteration of the microRNA network during the progression of Alzheimer's disease. EMBO Mol Med. 2013 Oct;5(10):1613-34. PMID: 24014289