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Oligodendroglial alterations in FTD caused by C9orf72 expansion
Author(s) -
Dolcet Sonia Sirisi,
QuerolVilaseca Marta,
DolsIcardo Oriol,
Pegueroles Jordi,
Montal Victor,
Muñoz Laia,
Torres Soraya,
Blesa Rafael,
Belbin Olivia,
Fortea Juan,
Clarimon Jordi,
Lleó Alberto
Publication year - 2020
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 - 10.1002/alz.040196
Subject(s) - c9orf72 , amyotrophic lateral sclerosis , frontotemporal dementia , trinucleotide repeat expansion , hippocampus , neuroinflammation , immunohistochemistry , prefrontal cortex , pathology , biology , neuroscience , medicine , dementia , disease , gene , allele , genetics , cognition
Background The 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. Method In 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. Result We 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. Conclusion These 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.