Abstracts

Rationale: Clinical and experimental data suggest an interaction between epilepsy and Alzheimer’s disease (AD), with seizures occurring in at least 20% of AD patients. A bidirectional relationship is also implied by clinical observation that the risk of cognitive impairment and even dementia is increased in some forms of chronic epilepsy such as temporal lobe epilepsy (TLE). AD is characterized by the accumulation of β-amyloid (Aβ) peptide in amyloid plaques, and hyperphosphorylated Tau proteins in neurofibrillary tangles. Soluble Aβ oligomers, including Aβ*56, have been shown to induce synaptic dysfunction and memory impairment in AD patients and mice. Previous studies reveal the presence of amyloid plaques in chronic TLE brain tissue, without understanding their origin. We hypothesize that the presence of amyloid plaques in TLE brains is due to an increase of the amyloidogenic processing -leading to Aβ production- of the amyloid precursor protein (APP). Here, we investigated TLE tissue to identify markers of the APP pathway, to promote future translational investigative research. Methods: We analyzed by Western blot surgically resected hippocampal tissue (mean=31 years, n=5) and temporal cortex (mean=32.3 years, n=9) obtained from TLE patients and postmortem samples from control subjects (mean=39.9 years, n=5). We measured the expression level of several markers of the amyloidogenic and non-amyloidogenic pathway of APP processing.  Results: In TLE hippocampus compared to controls, we observed a significant upregulation of the amyloidgenic pathway, with the increased expression of Aβ*56 (426% of controls, p Conclusions: We found an upregulation of the amyloidogenic processing of APP in TLE, leading to an increase of Aβ*56. Aβ*56, which may play a pathogenic role at the very beginning of AD, could act as potent seeds in TLE brains for prion-like seeding and propagation of the neuropathology, leading to potential later dementia. In TLE hippocampus the increase of the non-amyloidogenic pathway, downregulated during AD, may be a consequence of hyperexcitability. Indeed, APP and its non-pathogenic catabolites have been shown to play a role in neurogenesis, synaptic formation and transmission. Taken together, our results show that TLE patients may present a very-early AD-phenotype but associated with non-AD dysregulations probably linked to epileptogenesis. Funding: University Research Foundation. NIHR01NS031718. Control human tissue was obtained from University of Maryland Brain and Tissue Bank, which is a Brain and Tissue Repository of the NIH NeuroBioBank.