Shared molecular pathways found in Alzheimer's and epilepsy

By Dr. Priyom Bose, Ph.D.Reviewed by Benedette Cuffari, M.Sc.Feb 5 2024

A recent Acta Neuropathologica study identifies shared mechanisms between epilepsy and Alzheimer’s disease (AD) using proteomics.

Study: Similar brain proteomic signatures in Alzheimer’s disease and epilepsy. Image Credit: meebonstudio / Shutterstock.com

The complex relationship between AD and epilepsy

Several studies have shown that individuals with epilepsy are more likely to develop AD. Likewise, as compared to otherwise healthy individuals, those with epilepsy experience a rapid age-related cognitive decline and are at a greater risk of dementia.

AD patients are also at an increased risk of experiencing unprovoked seizures. In mouse studies on AD, anti-seizure medications have been shown to reduce cognitive impairment and improve spatial memory. 

In AD patients, seizures are associated with accelerated cognitive decline and more significant AD neuropathology, such as reduced brain weight, elevated white matter β-amyloid (Aβ) plaque pathology, and increased phosphorylated tau (pTau) expression. AD mouse models have shown that overexpressed Tau is associated with seizures. 

The morphology of pTau aggregates overlaps with AD and chronic traumatic encephalopathy. Some of the shared morphology include neuronal pre-tangles, neurofibrillary tangles (NFTs), extracellular deposits, astrocytic tau pathology, and subpial band staining.

Notably, epilepsy-related pTau pathology has not been observed in all experimental studies. Similarly, Aβ plaques have been identified in some epilepsy patients, but not all.

Increased levels of specific pTau have been associated with protective functions in AD patients and those with epilepsy, including reduced behavioral deficits and mortality. Although several studies have highlighted the bidirectional relationship that exists between AD and epilepsy, the shared pathophysiological changes between the two conditions are not clearly understood. 

About the study

The current study identified common protein differences in the brains of epileptic and AD patients based on publicly available comprehensive proteomic data on these diseases. Individuals with epilepsy were identified from the North American Sudden Unexpected Death in Epilepsy (SUDEP) registry.

The proteomic dataset analyzed comprised 777 proteins that were significantly altered in the hippocampal region of epileptic individuals. The microdissected tissue of the hippocampal region exhibited neuropathological lesions.

Although protein alterations in the dentate gyrus and frontal cortex of epileptic individuals have been documented, the current study only considered protein alterations in the hippocampus as a representative dataset of protein changes in epilepsy.

Protein alteration data in AD patients were obtained from NeuroPro, which included 5,311 altered proteins in humans with AD. Total tau interactors were identified in humans with advanced AD using co-immunoprecipitation of the Tau5-immunoreactive total tau protein technique. UniProt ID or Gene ID was used to compare protein datasets.

Study findings

Many common protein differences in AD and epilepsy brain tissue were identified, thus providing evidence for the existence of common molecular mechanisms shared between AD and epilepsy. In this regard, common pathological changes concerning mitochondrial and synapse dysfunction were observed.

The proteomic analysis revealed that tau could be the key mediator of protein differences in AD and epilepsy. Based on previous findings, tau-regulated protein changes in epilepsy could be governed by tau oligomers or monomers. This observation aligns with the finding that soluble tau oligomers are a toxic mediator in AD.

The study findings revealed that only specific pTau species are altered in epilepsy. More specifically, elevated levels of pTau217 and pTau231, but not pTau396/404, were observed in epileptic patients. Nevertheless, more research using larger cohorts is needed to validate this observation.

Elevated levels of both pTau217 and pTau231 were observed in the brains of patients with epilepsy and those in the early stages of AD. Importantly, this is the first study to identify pTau217 in epilepsy brain tissues.

In line with previous studies, tau appears to be the main upstream controller that causes reduced levels of multiple neuronal proteins, including axons, synapses, microtubules, and mitochondrial proteins in epilepsy.

Protein differences in both AD and epilepsy were not consistent, thus indicating the potential for distinct molecular mechanisms associated with this effect. An increase in ribosomal proteins in epilepsy was observed, which was not prominent in AD, thus suggesting an altered function of pTau in ribosomes in both conditions. Future studies are needed to elucidate the regulatory role of tau on ribosomal protein changes in epilepsy.

Conclusions

The current study provided evidence of the bidirectional relationship between AD and epilepsy, as many similar trends in protein dysfunction were observed in both diseases. Identifying the common molecular mechanism shared between epilepsy and AD could support the development of a therapeutic target for both diseases.