“Alzheimer’s disease treatment explored through optogenetic light stimulation”

Team unveils role of hippocampal inhibitory neurons in the early stages of Alzheimer’s disease

Results published in leading bioscience journal BMC Biology

▲ From left: Prof. Jeehyun Kwag (corresponding author), Kyerl Park (first author, Ph.D. program), 

Jaedong Lee (first author, Ph.D. program)

A team led by Professor Jeehyun Kwag of the KU Department of Brain & Cognitive Engineering found that brain oscillations and synaptic plasticity impairments exhibited in the early stage of Alzheimer’s disease can be restored by employing optogenetic light stimulation to adjust the activation of inhibitory neurons (parvalbumin and somatostatin interneurons) in the hippocampal network.

Funded by the Disease Overcoming Technology Development Project and National Dementia Research and Development Project of the Korea Health Industry Development Institute and the Human Frontier Science Program, the study was published in the world-renowned BMC Biology on January 15.

*Title of paper: “Optogenetic activation of parvalbumin and somatostatin interneurons selectively restores theta-nested gamma oscillations and oscillation-induced spike timing-dependent long-term potentiation impaired by amyloid β oligomers”

*URL: https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-019-0732-7

*Author information: Kyerl Park (first author, Korea University), Jaedong Lee (first author, Korea University), Hyun Jae Jang (co-author, Korea University), Blake A. Richards (co-author, University of Toronto), Michael M. Kohl (co-author, University of Oxford), and Jeehyun Kwag (corresponding author, Korea University)

Alzheimer’s disease, a neurodegenerative disorder that accounts for about 70% of dementia cases in Korea, causes memory loss through neural destruction and the collapse of neural circuits that are induced by the presence of amyloid beta peptides in the hippocampus. In particular, the presence of amyloid beta peptides in the hippocampus during the early stages of the disease is associated with brain wave and synaptic plasticity impairments. However, such impairments have not been addressed due to a lack of understanding of the underlying neural circuit mechanisms and an inability to selectively target and restore damaged circuits.

Professor Jeehyun Kwag’s team succeeded in restoring brain wave and synaptic plasticity impairments caused by amyloid beta peptides to normal levels by applying an optogenetic adjustment technique (inserting ion channels into specific neurons and selectively adjusting the activation of the neurons using light) to inhibitory neurons (parvalbumin and somatostatin interneurons) in the hippocampus.

Specifically, the team revealed that gamma oscillations (40-80 Hz) damaged by amyloid beta were restored to normal levels through the optogenetic activation of parvalbumin interneurons via light stimulation. In addition, this is the first report of successfully restoring synaptic plasticity impairments through the optogenetic activation of somatostatin interneurons via light stimulation.

In the study, the team showed for the first time that parvalbumin and somatostatin interneurons are selectively involved in brain wave and synaptic plasticity impairments during the early stages of Alzheimer’s and demonstrated the possibilities of selective optogenetic activation in the treatment of Alzheimer-related impairments and memory loss. Also of significance, the study identified specific inhibitory (GABAergic) neurons and their circuits as potential therapeutic targets, instead of excitatory neurons, as was the case in past research on Alzheimer’s disease.

[Fig. 1] Hippocampal gamma oscillations impaired by amyloid beta oligomers (AβO), a hallmark of Alzheimer’s disease, in the hippocampal network restored to normal levels through optogenetic activation of parvalbumin interneurons (PV)

[Fig. 2] Hippocampal synaptic plasticity impaired by AβO restored to normal levels through optogenetic activation of somatostatin interneurons (SST)