Rajani RM, Ellingford R, Hellmuth M, Harris SS, Taso OS, Graykowski D, Lam FK, Arber C, Fertan E, Danial JS, Swire M, Lloyd M, Giovannucci TA, Bourdenx M, Klenerman D, Vassar R, Wray S, Sala Frigerio C, Busche MA. Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer's disease. PLoS Biol. 2024 Jul;22(7):e3002727. Epub 2024 Jul 23 PubMed.
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Brigham and Women's Hospital, Harvard Medical School
This pair of studies from the Busche and Nave groups nicely replicate each other’s key finding: that oligodendrocytes, not just excitatory neurons, contribute to amyloid plaque formation in an APP knock-in mouse model. In my opinion, the most striking conclusion is how modest the contribution of oligodendrocytes is to plaque formation, despite their high-level expression of amyloidogenic genes and the ability of iPSC-derived oligodendrocytes to produce plenty of Aβ peptide.
In both studies, selective deletion of β-secretase from oligodendrocytes only reduced plaques by around 25 percent, whereas neuronal deletion almost totally prevented plaques. We also know that the white matter of human AD, where oligodendrocytes abound, has very few plaques compared to the neuron-rich cortex. This might mean that the gray matter interstitial microenvironment is more amyloidogenic than white matter despite similar production rates of nascent Aβ peptide. Notwithstanding the effects of total cell density, it might not be just how much Ab a cell produces, nor just the Aβ42:40 ratio, but where the Aβ ends up and what it interacts with, that determines plaque formation. In addition to targeting Aβ and its processing pathway, therapeutics that target and modify this interstitial microenvironment (microglia, astrocytes, APOE) may thus succeed early in the disease.
View all comments by Andrew SternGerman Center for Neurodegenerative Diseases (DZNE)
Both these studies are outstanding and provide excellent in vivo evidence for a role of oligodendrocytes in plaque formation and neuronal hyperactivity in AD. Moreover, both studies highlight that BACE1 is not only active in neurons—the cell type most previous studies focused on—but also in oligodendrocytes. This adds to our increasing knowledge of non-neuronal BACE1 functions, which also include microglia (Singh et al., 2022; Singh et al., 2022) and potentially other brain cell types as well.
Given that BACE1 cleaves not only APP–at least in neurons—we now need to consider that BACE1 may have additional substrates/functions in the other brain cell types that still need to be identified. Both studies raise the possibility of oligodendrocyte-specific inhibition of BACE1. It would be very valuable to test such an approach. This may be a means to avoid the cognitive worsening side effect of high doses of BACE1-targeted inhibitors previously used in clinical trials, provided that BACE1 inhibition in oligedendrocytes does itself contribute to the cognitive worsening.
Another approach to prevent the cognitive worsening, which is currently pursued in the field, is to reduce the dose of the BACE1-targeted inhibitors to less than 50 percent BACE1 inhibition (McDade et al., 2021). Such a global, but mild, BACE1 inhibition appears to sufficiently reduce Aβ in a prevention setting while avoiding inhibition of (potentially) essential BACE1 functions in the different brain cell types, including oligodendrocytes.
References:
Singh N, Das B, Zhou J, Hu X, Yan R. Targeted BACE-1 inhibition in microglia enhances amyloid clearance and improved cognitive performance. Sci Adv. 2022 Jul 22;8(29):eabo3610. Epub 2022 Jul 20 PubMed.
Singh N, Benoit MR, Zhou J, Das B, Davila-Velderrain J, Kellis M, Tsai LH, Hu X, Yan R. BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1. Sci Adv. 2022 Jun 17;8(24):eabo1286. PubMed.
McDade E, Voytyuk I, Aisen P, Bateman RJ, Carrillo MC, De Strooper B, Haass C, Reiman EM, Sperling R, Tariot PN, Yan R, Masters CL, Vassar R, Lichtenthaler SF. The case for low-level BACE1 inhibition for the prevention of Alzheimer disease. Nat Rev Neurol. 2021 Nov;17(11):703-714. Epub 2021 Sep 21 PubMed.
View all comments by Stefan LichtenthalerMake a Comment
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