Rossi SL, Bovenkamp DE. Are oligodendrocytes the missing link in Alzheimer’s disease and related dementia research?. Mol Neurodegener. In press.
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Rossi SL, Bovenkamp DE. Are oligodendrocytes the missing link in Alzheimer’s disease and related dementia research?. Mol Neurodegener. In press.
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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.
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