Neuropathological assessment of beta-amyloid and tau pathology in human focal cortical dysplasia with drug-resistant epilepsy
thesisposted on 28.07.2021, 01:27 by Alisha S AroorAlisha S Aroor
Rationale: Focal cortical dysplasia (FCD) is a neurodevelopmental disorder that is associated with abnormal cortical development and is one of the most common drug-resistant epilepsies. The mechanistic target of rapamycin (mTOR) pathway is a highly complex pathway
associated with cell proliferation, synaptic plasticity, neuroinflammation, and cortical development. Hyperactivation of this pathway has also been implicated in hyperexcitability, seizures, and accumulation of beta-amyloid (Aβ) plaques and neurofibrillary tangles (NFT) through hyperphosphorylation of tau. Interestingly, Aβ and hyperphosphorylated tau have been reported in both rodent models and human patients of temporal lobe epilepsy (TLE) and FCD however, the mechanisms through which this occurs are still yet to be defined. Therefore, to identify the possible link between Aβ and tau pathology in FCD, we determined the spatial distribution and protein levels of Aβ and phosphorylated tau (p-tau) along with mTOR signaling
molecules. We hypothesized that there would be presence of Aβ and tau pathology as well as an increase in Aβ and p-tau protein levels that would be correlated with hyperactivation of the mTOR and GSK3 signaling pathways in tissue biopsies from human FCD patients compared to brain tissues from non-epileptic (NE) individuals.
Methods: Cortical brain samples surgically resected from patients with FCD were used and compared to NE samples surgically resected from glioblastoma patients with no history of seizures or epilepsy. Immunostaining was used to determine the distribution of phosphorylation of S6 (p-S6), a marker for mTOR activation, and NeuN, a marker for neurons, along with Aβ and p-tau. Additionally, western blotting (WB) was used to determine the levels of mTOR signaling through p-S6 and GSK3 (p-GSK) along with Aβ and p-tau.
Results: We found cortical dyslamination, mTOR activation, p-tau, and Aβ accumulation in cortices of patients with FCD with drug-resistant epilepsy. However, we did not find a
significant difference in the protein levels of p-S6 (p = 0.422), p-GSK3 (p = 0.947), p-tau (p = 0.649), and Aβ (p = 0.852) in cortical tissue homogenates derived from FCD patients when compared to those of NE samples. Additionally, we did not find sex differences in the protein
levels of p-S6 (p = 0.401), p-GSK3 (p = 0.331), p-tau (p = 0.935), and Aβ (p = 0.526). There was no significant correlation between age and p-S6 (p = 0.920), age and p-GSK3 (p = 0.089), age and p-tau (p = 0.956), and age and Aβ (p = 0.889). Moreover, there was no significant correlation between mTOR activation (p-S6), Aβ (p = 0.586) and p-tau (p = 0.059) nor GSK3 activation (p-GSK3), Aβ (p = 0.326), and p-tau (p = 0.715). Lastly, there was no significant correlation within the mTOR and GSK3 pathway activation within the same patients (p = 0.602).
Conclusion: These data suggest that mTOR hyperactivation occurs alongside the presence of Aβ and tau pathology. However, several unknown factors such as medical and medication history may be altering the expression or suppression of these proteins. Additionally, there may be alternative pathways that crosstalk with mTOR signaling therefore influencing Aβ and tau pathology in FCD patients with drug-resistant epilepsy. Further investigation will need to be conducted to understand the detailed mechanisms through which Aβ and tau pathology occur in