Research Spotlight: Optogenetic GABA Neuron Targeting Improves Alzheimer's Pathology

Ksenia V. Kastanenka, PhD, an investigator in the Department of Neurology and an assistant professor of Neurology at Harvard Medical School, is the senior author of a recently published paper in Molecular Degeneration, Sleep restoration by optogenetic targeting of GABAergic neurons reprograms microglia and ameliorates pathological phenotypes in an Alzheimer’s disease model.

What Question Were You Investigating?

Could increasing brain cell activity (stimulation of inhibitory interneurons) restore deep, non-rapid eye movement (NREM) sleep quality, improve memory consolidation and slow the pathological progression of Alzheimer’s disease in a mouse model?

What Methods Did You Use?

In our study, we employed a commonly used mouse model for Alzheimer's disease (AD), known as APPswe/PS1dE9 (APP).

Taking a new approach, we used state-of-the-art optogenetics (a light-based technique for controlling the activity of neurons) to directly and specifically stimulate GABAergic inhibitory interneurons to restore sleep-dependent slow wave activity (SWA) in living mice.

Targeting restoration of SWA to slow AD is a unique therapeutic approach. Furthermore, advanced techniques such as multiphoton microscopy, flow cytometry, and EEG/EMG telemetry for sleep analysis were utilized to elucidate mechanisms by which NREM sleep prevents pathological accumulation of amyloid β (Aβ) in AD.

What Did You Find?

At baseline, the APP mouse model exhibited impairments in sleep, including decreased time spent in NREM sleep, decreased delta power and increased sleep fragmentation compared to nontransgenic (NTG) control mice.

Optogenetic stimulation of cortical GABAergic interneurons increased SWA and rescued sleep impairments in APP mice.

Furthermore, it slowed Alzheimer's disease progression by reducing amyloid deposition, normalizing neuronal calcium homeostasis and improving memory function.

What Are the Implications?

Sleep disruptions, especially reductions of NREM sleep and SWA, are associated with Alzheimer's disease, even in the preclinical stages of the disease.

Reduced NREM sleep may drive the development of AD neuropathology by increasing Aβ production and promoting a dysregulated state of the innate immune cells of the brain--microglia.

Our findings propose the targeting of inhibitory interneurons as a viable therapeutic option for enhancing sleep-dependent memory and promoting microglia-mediated innate immune response in clearing deleterious pathological burden in patients with Alzheimer's disease.

What are the Next Steps?

This work opens the door to a range of therapeutic strategies to be pursued in future studies, including therapeutic targeting of interneurons and their signaling mechanisms, microglia and neuroinflammation, as well as sleep-dependent brain rhythms.

Interneurons and microglia can also be targeted with pharmacological agents which are easier to translate to clinical care.

We hope to pursue translational approaches to restore circuit function using non-invasive and invasive stimulation modalities, including acoustic stimulation and transcranial Direct Current Stimulation (tDCS).

Paper Cited:

Zhao, Q., Maci, M., Miller, M. R., Zhou, H., Zhang, F., Algamal, M., Lee, Y. F., Hou, S. S., Perle, S. J., Le, H., Russ, A. N., Lo, E. H., Gerashchenko, D., Gomperts, S. N., Bacskai, B. J., & Kastanenka, K. V. (2023). Sleep restoration by optogenetic targeting of GABAergic neurons reprograms microglia and ameliorates pathological phenotypes in an Alzheimer's disease model. Molecular neurodegeneration, 18(1), 93. https://doi.org/10.1186/s13024-023-00682-9

About Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. Massachusetts General Hospital is a founding member of the Mass General Brigham healthcare system.