Alzheimer’s disease (AD) is widely believed to be driven by the accumulation of amyloid-β (Aβ) peptide produced by excitatory (ExNs) neurons. A new study in Nature Neuroscience provides the first in vivo evidence that oligodendrocytes (OL) — a glial cell type — also contribute to Aβ plaque formation in AD.

After confirming that mouse and human OL express key amyloidogenic pathway genes (APP, BACE1, PSEN1 and PSEN2) and the amyloid precursor protein (APP), the investigators generated new AD mouse lines to assess the contribution of ExNs and OL to Aβ plaque burden. To create the models, the team crossed APPNLGF knock-in mice that express a humanized mutated APP in the endogenous App locus with Bace1fl/fl mice to conditionally knock out Bace1 — the rate-limiting enzyme in Aβ generation — in OLs and dorsal telencephalic ExNs, using cell-type-specific Cre drivers.

In toto imaging of amyloid plaques in the brains of 6-month-old mice using light-sheet microscopy revealed that plaque burden was reduced by > 95% in ExN-Bace1cKO;AD animals and by ~ 30% in OL-Bace1cKO;AD mice compared to non-Cre AD control mice. These results indicate that although dorsal telencephalic neurons are the predominant source of local and distal Aβ plaques, OLs also contribute to Aβ plaque burden.

In addition, analysis of 12-month-old ExN-Bace1cKO;AD mice revealed considerable plaque burden, which suggests that with enough time, plaques can still be formed by Aβ that is derived from other cell types than ExNs.

These findings open new avenues for the development of therapeutics based on the selective targeting of BACE1 in OLs as an alternative to widespread BACE1 inhibition, which has shown adverse effects in clinical trials. Identifying the mechanisms that slow down Aβ generation in OLs compared to neurons, despite the abundance of processing substrates and enzymes, could also pave the way for novel therapies targeting Aβ generation.

Original reference: Sasmita, A.O et. Nat. Neurosci. doi: 10.1038/s41593-024-01730-3 (2024)