Insulin resistance in the brain may link Alzheimer’s and epilepsy

Researchers from the University of São Paulo (USP) in Brazil have succeeded in an animal model that influences the process of insulin resistance in the brain both Alzheimer’s disease and epilepsy and a clutch factor between the two diseases.

The work, supported by FAPESP, confirms clinical evidence that people with epilepsy run a greater risk of developing Alzheimer’s disease as they get older. It is also not uncommon that people with Alzheimer’s disease have attacks.

“Naast het aantonen dat insulinesignalering in de hersenen, wanneer veranderd, zowel epilepsie als de ziekte van Alzheimer beïnvloedt, versterkt de studie het idee dat de ziekte van Alzheimer nog complexer is en daarom een ​​​​bredere therapeutische benadering nodig heeft die zich richten op één kenmerk van de ziekte van de ziekte. Ribeirão Preto Medical School (FMRP-USP), directeur van het laboratorium of neurophysiology and experimental neuroethology and corresponding author of the article published in the Journal of Neural Transmission.

Alzheimer’s disease is a complex, multifactorial neurodegenerative disease for which there is no remedy and no known cause. Under the various hypotheses to explain its beginning, the amyloid cascade stands out, according to which the deposit of beta-amyloid plaques in the brain is the initial and critical event that causes a series of processes that culminate in neuronal death, synapse loss and ultimately dementia.

This theory, formulated in 1992, has led Alzheimer’s research in recent decades.

Other important hypotheses are a decrease in acetylcholine, a neurotransmitter that is essential for memory and neuro inflammation, which hinders communication between neurons and can be activated by the accumulation of amyloid peptides in the brain. In addition, hyperphosphorylering of the Tau protein, the second main biiomarker of Alzheimer’s disease, leads to the formation of “tangles” in brain cells, which affects their function and contributes to the progression of the disease.

“Currently, the drugs that are most used to treat Alzheimer’s are used [anticholinesterase and antiglutamatergic drugs] have low effectiveness and are only symptomatic. And cases of people with beta-amyloid plaques in the brain [the result of the deposition of amyloid peptides] Without Alzheimer’s symptoms have already been described, “says the researcher.

Metabolic

Another hypothesis to explain the beginning of Alzheimer’s, emphasized by Garcia-Cairasco, is that the process of cerebral insulin resistance leads to neuronal damage and defective synaptic plasticity in a brain area called the Hippocampus. Insulin resistance of the brain could even influence the cholinergic function, increasing the risk of neuro inflammation and neurodegeneration and causes the production and accumulation of beta-amyloid and tau proteins in brain tissue.

It is worth noting that although patients with diabetes have a higher risk of Alzheimer’s, it is possible to have central insulin resistance without having type 1 or type 2 diabetes.

According to this hypothesis, which is not yet a consensus with experts, Alzheimer’s is due to a kind of diabetes called type 3, which describes a state of insulin resistance in the brain.

Epilepsy, on the other hand, is a group of disorders characterized by recurring and spontaneous attacks (convulsive or non-convulsive), with a higher prevalence in children and older adults. One of the various factors that cause epileptic attacks is a low blood sugar (hypoglycaemia). The cause of the disease can also be genetic or be related to brain trauma, autoimmune disorders, metabolic problems and infectious diseases.

There are scientists who exclusively associate Alzheimer’s with neuro inflammation, changes in neurotransmitters or type 3 diabetes. We believe that Alzheimer’s can be classified as a much more complex disease and that a deeper understanding of the relationship with epilepsy and insulin resistance can help us understand one of these factors related to the causality of the disease. “

Norberto Garcia-Cairasco, Professor at the Ribeirão Preto Medical School (FMRP-Susp)

The study is one of the first to show a direct connection between insulin resistance in the brain and increased sensitivity to attacks. Moreover, the work is part of a larger project that already won two excellent scientific prizes in 2024 – the Aristides Leão Award (best paper in the primary area), at the 40th Brazilian congress of the Brazilian congress of the Brazilian epilepsy.

It looks like an epileptic attack

In order to achieve these results, the FMRP-SuSP researchers discovered that rats micro-injected intracerebrally with streptozotocin-a chemical substance that is used to induce alzheimer’s disease.

“To test the type 3 diabetes hypothesis in an animal model, we injected the rodents with streptozotocin, a connection that is known to cause and used this insulin resistance to model diabetes and Alzheimer’s disease. Surprisingly, some animals were held in one, it had been posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted, posted. In a heat kept in a heat, it was one of the study.

The opposite was also observed: rats of the Wasterar -Audiogenic Rat (war) tribe, genetically manipulated to study epilepsy, also began to show molecular changes to Alzheimer’s disease, such as hyperphosest forylation of the tau -protein and a decrease in insulin receptors in the hipocampus.

A single dose of the drug injected into rodents with epilepsy and Alzheimer’s disease not only induced brain resistance against insulin, but also deteriorated the memory of the rodents and increased the frequency and severity of attacks.

“In addition to memory shortages, we have found that this model shows an increased sensitivity to audiogenic attacks, along with raised neuronal activation in brain areas that are rich in insulin receptors. These findings reinforce the idea that the resistance of the brain insulin plays a crucial role in the most important mechanisms of the most important mechanisms of the most important mechanisms of the most of the of the most of the of the most of the of the of the Mechanism and Kanheh and Kanheh and Kanheh and Kanheh and Kanheh and Kanheh and Kanheh and Kanhe and Kanhe and Kanheh and Kanheh and Kanheh and Kanheh and Kanheh and Kanh and Kanheh and Kanheh and Kanheh and Kanheh and Kanhteh and Kanhteh and Kanhteh and Kanheh and Kanhtehte’s Alhepsepsepsie and Kanh From the disease, “says Alves. “

“Moreover, the results in the war tribe emphasize the importance of the genetic background in shaping the response to treatment, which suggests that intrinsic characteristics can influence perturbations in insulin signaling that influence disease progression,” the researcher concludes.

It is worth noting that the tribe of Rats with Epilepsy and Alzheimer’s disease was genetically developed at FMRP-SPP to the Rat, Resource and Research Center (RRRC) at the University of Missouri (United States), where it is currently available for researchers from all over the world who want to carry out experiments.

Before being served, the tribe was remediated in the multidisciplinary center for biological research in the field of science in laboratory animals (CEMIB) of the State University of Campinas (Unicamp) to overcome international health barriers.

The group continues to study the relationship between the two diseases. Through a study supported by FAPESP and carried out in collaboration with the epilepsy surgery center (CireP) of the General and School Hospital (Das Clínicas hospital) of FMRP-Susp, they will study the study carried out on rats performed using tissues of patients have undergone an operation).

The variation in gene and protein expression in the cells of these patients will also be analyzed using proteomic and transcriptomic techniques in a different collaboration with researchers from Harvard University in the United States.