University of Eastern Finland (Finland) Researchers aim to treat Alzheimer’s disease by restoring interneuron function
Jane and Aatos Erkko Foundation has awarded a 90,000 euro grant to Docent Juzoh Umemori for a research project aiming to alleviate Alzheimer’s disease symptoms by restoring the function of parvalbumin-positive interneurons. Umemori leads a research group at the A. I. Virtanen Institute at the University of Eastern Finland and is a visiting researcher at the University of Helsinki.
Alzheimer’s disease (AD) is the most common neurodegenerative disorder associated with progressive cognitive deficits and memory loss. At present, there is no treatment available that would halt or even slow down the progression of the disease. This is mainly due to still incomplete understanding of the complex disease process. Recent research suggests that brain interneuron hypofunction may have a key role in the disease.
Professor Heikki Tanila’s and Professor Asla Pitkänen’s research groups at the A. I. Virtanen Institute have been among the first ones in the world to reveal the connection between AD and epilepsy. They observed epileptic seizures in transgenic mice at an age when first amyloid plaques can be detected in the brain. Hypofunction of parvalbumin-positive interneurons, a well-known to cause epileptic seizures, has been documented in the brains of AD model mice and human AD patients. In the light of these observations, hypofunctional parvalbumin-positive interneurons appear a promising new therapeutic target for AD. However, the causal relationship between epilepsy, progressive memory loss and dysfunction of parvalbumin-positive interneurons is still unknown.
Brain-derived neurotrophic factor (BDNF) regulates neuronal survival, differentiation and plasticity by activating the receptor tyrosine kinase TrkB, and is thereby involved in memory formation. A previous study showed that crossing transgenic mice overexpressing TrkB with AD model mice subtly alleviated their memory loss. However, a long-lasting, stronger and cell-specific TrkB induction would be needed for a significant therapeutic effect in the future. Umemori has recently developed optically activatable TrkB (optoTrkB) and found that its activation in parvalbumin-positive interneurons drastically changed network plasticity for a long time.
In the project funded by Jane and Aatos Erkko Foundation, the research group aims to restore the function of parvalbumin-positive interneurons by transducing AD model mice first with AAV viral vectors expressing modified TrkB, and at a later stage, with AAVs carrying optoTrkB which will be activated by light. These manipulations are expected to ameliorate memory impairment, epileptic activity or both via restoring the function of parvalbumin-positive interneurons.
The study will provide a new targeted therapeutic concept and methodology that can be applied to human studies in the future. Clinically, it could lead to new and effective treatments of AD with both symptomatic and disease-modifying effects.