Researchers from the University of São Paulo (USP) in Brazil have demonstrated in animal models that insulin resistance in the brain could be a key link between Alzheimer’s disease and epilepsy. Their study, funded by FAPESP and recently published in the Journal of Neural Transmission, provides fresh insights into how these two complex neurological conditions may be intertwined. Professor Norberto Garcia-Cairasco, director of the Laboratory of Neurophysiology and Experimental Neuroethology, highlighted that this discovery bolsters existing evidence that people with epilepsy are more likely to develop Alzheimer’s disease as they age and that seizures are common in those with Alzheimer’s.
Alzheimer’s disease is a multifactorial neurodegenerative condition with no known cure, long associated with the amyloid cascade hypothesis. This theory suggests that the accumulation of beta-amyloid plaques in the brain triggers neuronal damage and cognitive decline. However, other theories have emerged, focusing on the role of tau protein tangles, decreased acetylcholine (a neurotransmitter essential for memory), and neuroinflammation. These factors all contribute to the complex pathology of Alzheimer’s, suggesting that a broader therapeutic approach is needed beyond just targeting beta-amyloid.
Another area of interest is the so-called “type 3 diabetes” hypothesis, which posits that insulin resistance within the brain damages neurons and disrupts synaptic plasticity, especially in the hippocampus. Garcia-Cairasco and his team believe this cerebral insulin resistance can impair cholinergic function, leading to neuroinflammation and increasing the accumulation of beta-amyloid and tau proteins accumulation. Importantly, central insulin resistance can occur even without systemic diabetes, hinting at a unique pathway of neurodegeneration.
The researchers conducted experiments in rats, injecting them with streptozotocin to induce insulin resistance in the brain. They found that these rats not only developed Alzheimer ’s-like symptoms but also showed an increased susceptibility to seizures after exposure to high-intensity sounds. Conversely, genetically engineered rats predisposed to epilepsy (Wistar Audiogenic Rat strain) exhibited molecular markers typical of Alzheimer’s disease, such as tau hyperphosphorylation and reduced insulin receptor activity in the hippocampus.
A single dose of streptozotocin in these rats resulted in both memory deficits and a heightened tendency for seizures. This suggests that insulin resistance in the brain does not just affect memory and cognitive function but increases neuronal excitability, making seizures more likely. The team also noted that genetic differences influence how the brain responds to insulin disruption, hinting at a potential for personalised approaches to treatment in the future.
This critical work has already garnered recognition, winning the Aristides Leão Award at the Brazilian Epilepsy League Congress and the Best Poster Award in Geriatrics at the Brazilian Alzheimer’s Congress. The unique strain of rats developed in this study has been shared with researchers worldwide, offering a new model for studying the complex link between Alzheimer’s disease and epilepsy. Such collaborations may pave the way for more targeted therapies that address insulin resistance in the brain, bringing fresh hope for treating these debilitating conditions.
More information: Norberto Garcia-Cairasco et al, Insulin signaling disruption exacerbates memory impairment and seizure susceptibility in an epilepsy model with Alzheimer’s disease-like pathology, Journal of Neural Transmission. DOI: 10.1007/s00702-025-02896-1
Journal information: Journal of Neural Transmission Provided by Fundação de Amparo à Pesquisa do Estado de São Paulo
