Sharon O, Chen X, Dude J, Shah VD, Ju Y-E, Jagust WJ, Walker MP. Tau pathology leads to lonely non-traveling slow waves that mediate human memory impairment. 2024 May 22 10.1101/2024.05.22.595043 (version 1) bioRxiv.
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University College London
I think this is a fascinating and timely research article, demonstrating that the propagation of slow waves across the neocortex during sleep is impaired in older individuals. This impairment is correlated to the degree of tau tangle pathology in the brain, and the authors’ analyses further suggest that the impairment of slow waves is related to deficits in overnight memory consolidation. Slow wave propagation is a highly conserved phenotype, and I am intrigued that this novel human dataset aligns very closely with preclinical papers from our group (Busche et al., 2015; Keskin et al., 2017).
In our work with APP mouse models, we show that the propagation of slow waves is similarly impaired, and this impairment caused memory deficits in the mice. We found that the slow waves, which originate from deeper layers of the cortex, were more localized and failed to propagate into surrounding tissue in the mice.
Importantly, this deficit was not dependent on amyloid plaques, consistent with the current human study, but was instead caused by soluble Aβ. We demonstrated that suppressing soluble Aβ rescued the wave deficits, while direct administration of soluble Aβ promoted them. Given that soluble Aβ oligomers cannot yet be directly measured in the human brain, which is a gap, this aspect obviously could not be included in the current analyses. Nonetheless, it is highly likely that the study participants have soluble Aβ in their brains.
Furthermore, in our studies, we showed that impairments in slow-wave propagation and associated memory deficits in mice could be rescued by enhancing GABAergic inhibition. It would be intriguing to explore if a similar therapeutic approach could be tested in human participants.
References:
Busche MA, Kekuš M, Adelsberger H, Noda T, Förstl H, Nelken I, Konnerth A. Rescue of long-range circuit dysfunction in Alzheimer's disease models. Nat Neurosci. 2015 Nov;18(11):1623-30. Epub 2015 Oct 12 PubMed.
Keskin AD, Kekuš M, Adelsberger H, Neumann U, Shimshek DR, Song B, Zott B, Peng T, Förstl H, Staufenbiel M, Nelken I, Sakmann B, Konnerth A, Busche MA. BACE inhibition-dependent repair of Alzheimer's pathophysiology. Proc Natl Acad Sci U S A. 2017 Aug 8;114(32):8631-8636. Epub 2017 Jul 24 PubMed.
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