GABA Deficits and Sleep Disruption in Early Alzheimer Disease

CONFERENCE REPORTER

Ksenia Kastanenka, PhD, discussed her laboratory's research into sleep impairments in early Alzheimer disease, focusing on mouse model findings that identify GABAergic inhibitory tone deficits as a candidate molecular mechanism.¹

Kastanenka noted that sleep disturbances—specifically difficulty falling and staying asleep—are recognized features of early-stage Alzheimer disease in humans. Her group subsequently demonstrated that these sleep impairments are recapitulated in mouse models of amyloidosis. The work was published in Molecular Neurodegeneration in 2023 and utilized the APP/PS1 mouse model, which overexpresses a human amyloid precursor protein gene carrying the Swedish mutation alongside the deltaE9 mutation in the presenilin gene.² Affected animals exhibited shortened non-rapid eye movement (NREM) sleep duration and prolonged wake periods, mirroring the human phenotype.

Having established the sleep deficit phenotype, Kastanenka's group went on to investigate the underlying molecular mechanisms. They found significant downregulation of inhibitory tone, specifically of GABA-A and GABA-B receptors, in the APP/PS1 model at early stages of Alzheimer disease progression. Critically, exogenous GABA administration to the brains of these animals rescued a sleep-dependent brain rhythm characteristic of deep NREM sleep: the slow oscillation. Kastanenka interpreted this finding as evidence that the relevant neural circuits are in a state of hyperexcitability, with GABAergic deficit as the primary driver.

Dr Kastanenka is assistant professor at Mass General Brigham and affiliated with Harvard Medical School.

References

1. Xu Y, Zhao M, Han Y, et al. GABAergic inhibitory interneuron deficits in Alzheimer's disease: implications for treatment. Front Neurosci. 2020;14:660.

2. Yeapuri P, Machhi J, Lu Y, et al. Amyloid-B specific regulatory T cells attentuate Alzheimer’s disease pathobiology in APP/PS1 mice. Mol Neurodegen. 2023;18:97.