Marta Querol Vilaseca, Spain
, Institut d'Investigacions Biomèdiques Sant Pau -Hospital de la Santa Creu i Sant Pau Neurology, Memory UnitAuthor Of 2 Presentations
OLIGODENDROGLIAL ABNORMALITIES IN FTLD-C9ORF72
Abstract
Aims
The aim was to identify alterations in oligodendrocyte cells in frontotemporal dementia caused by C9orf72 expansion (FTLD-C9).
Methods
Using conventional immunohistochemistry we characterized the pathological mechanisms associated with C9orf72 expansion (dipeptide proteins repeat, polyGA, polyGP and polyGR, RNA foci and TDP-43 pathology). We also performed neuropathological studies for Myelin Basic Protein (MBP), a major constituent of the CNS myelin, in the frontal cortex and hippocampus of FTLD-C9orf72 cases to determine a potential specific phenotype for oligodendrocyte cells. We used postmortem samples of patients with a C9orf72 expansion and confirmed FTLD-TDP pathology (n=22), sporadic FTLD-TDP (n=8) and healthy controls without neuropathological alterations (n=10). To quantify the immunoreactivity of MBP we used an in-house semi-automated algorithm. We also performed Western Blot experiments to determine the protein levels of MBP in these three different pathological groups.
Results
We found a significant decrease of MBP immunoreactivity in the grey and white matter of the frontal cortex in the FTLD-C9 group compared to sporadic FTLD-TDP and healthy control groups. We did not find a correlation between MBP expression and the number of DPRs or RNA foci. We observed a trend towards a negative correlation between MBP and TDP-43 pathology in the frontal cortex. We also found a decrease in the MBP protein levels in the grey matter of the frontal cortex in the FTLD-C9 group.
Conclusions
Our results suggest an oligodendroglial dysfunction associated with the C9orf72 expansion. Oligodendroglial dysfunction might constitute an important and so far neglected pathophysiological event.
APP-C99 ACCUMULATION IN SYNAPSES IN ALZHEIMER'S DISEASE
Abstract
Aims
Our group and others have recently shown that the Amyloid Precursor Protein (APP) C-terminal fragment of 99 amino acids (APP-C99) accumulates in the brain of AD animal models and of sporadic and autosomal-dominant AD patients. The aim was to determine whether APP and APP-C99 accumulates within synapses in AD.
Methods
We applied Array Tomography (AT) in human AD tissue to investigate APP localization at synapses. We also isolated synaptosomal fractions from 40 frozen frontal cortex tissue blocks provided by the Neurological Tissue Brain Bank-IDIBAPS. We used postmortem brain samples of patients with sporadic AD (n=10), autosomal-dominant AD (n=10), Down syndrome with AD (n=10) and healthy controls without AD neuropathology (n=10). Using a commercially available assay (APP-B-CTF: IBL America) we measured APP-C99 levels in cerebral homogenates and in synaptosomal fractions across groups.
Results
Using array tomography we found that APP is localized at pre- and post-synaptic compartments in human AD brains. Our results demonstrated that there is a significant increase of APP-C99 accumulation (~2-fold) in synaptosomal fractions compared with brain homogenates in healthy controls. APP-C99 is also significantly increased in synaptosomal fractions of AD cases compared with healthy controls.
Conclusions
Our data reveal that APP is present and that APP-C99 accumulates, in synapses in AD. Our results suggest a potential role of APP-C99 in the synaptic damage in AD. Therapies aimed at mitigating APP-C99 accumulation could be potentially beneficial in AD.