Oligodendroglial alterations in FTD caused by C9orf72 expansion

Abstract

AbstractBackgroundThe most frequent genetic cause of Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) is the hexanucleotide repeat expansion in the C9orf72 gene. Until now, three different mechanisms have been proposed to explain its pathogenic effects: i) loss of function of the C9orf72 protein, ii) toxic gain of function from sense and antisense C9orf72 repeat RNA, or iii) toxic gain of function from Dipeptide Repeat Proteins. Another important hallmark associated with C9orf72 mutations is the TDP43 accumulation in neurons and glia. As in other neurodegenerative diseases, neuroinflammation is a common feature in FTD; however, the specific role of the innate immune system in FTD associated to specific subtypes of the disease is unknown.MethodIn this study, we investigated changes in the pattern of different glial markers (GFAP, YKL‐40, Iba‐1 and MBP) using immunohistochemistry in the frontal cortex and hippocampus of a cohort of 23 cases diagnosed with C9‐FTD/ALS with TDP43 pathology (C9‐FTD), 8 cases diagnosed with sporadic‐FTD TDP43 (sFTD) and 9 healthy controls (HC). Different in‐house semi‐automated MATLAB algorithms were developed and were used to quantify the immunoreactivity of these different markers.ResultWe found a significant increase of GFAP, YKL‐40 and Iba1 immunoreactivity in C9‐FTD and in the sporadic group compared with a group of healthy controls both in frontal cortex and hippocampus. We also found a decreased of MBP protein immunoreactivity in the group of C9‐FTD samples, both in grey and white matter from the frontal cortex, compared to control and sporadic group of samples. In C9‐FTD group we found a negative correlation between MBP and TDP43.ConclusionThese results indicate that FTD caused by C9orf72 is associated with myelin loss likely caused by the mutation or its distinct pathology. Understanding these biological processes will help to identify specific pathways associated with this FTLD subtype and help in the development of new therapeutic strategies implicating oligodendroglial cells as a target to reduce the disease progression and improve quality of life of FTD with C9orf72 expansion patients.