Good news!
"Lecanemab, sold under the name Leqembi, is a monoclonal antibody therapy for Alzheimer's disease that clears toxic amyloid plaques and delays cognitive decline. ...
They showed that the "Fc fragment" of this monoclonal antibody is essential for engaging microglia—the immune cells of the brain—thus initiating the cellular machinery needed for plaque removal. This is the first direct mechanistic explanation for how this class of therapies works. It clarifies uncertainties in the field and offers a blueprint for developing safer, more effective Alzheimer's treatments. ...
They identified key cellular machinery needed to clear the amyloid plaques: namely, phagocytosis and lysosomal activity.
Without the Fc fragment, none of these critical cellular processes were triggered. ... uncovered a microglial gene program, marked by strong expression of the gene SPP1. ..."
From the abstract:
"Controversies over anti-amyloid immunotherapies underscore the need to elucidate their mechanisms of action.
Here we demonstrate that Lecanemab, a leading anti-β-amyloid (Aβ) antibody, mediates amyloid clearance by activating microglial effector functions.
Using a human microglia xenograft mouse model, we show that Lecanemab significantly reduces Aβ pathology and associated neuritic damage, while neither fragment crystallizable (Fc)-silenced Lecanemab nor microglia deficiency elicits this effect despite intact plaque binding.
Single-cell RNA sequencing and spatial transcriptomic analyses reveal that Lecanemab induces a focused transcriptional program that enhances phagocytosis, lysosomal degradation, metabolic reprogramming, interferon γ genes and antigen presentation.
Finally, we identify SPP1/osteopontin as a major factor induced by Lecanemab treatment and demonstrate its role in promoting Aβ clearance.
These findings highlight that effective amyloid removal depends on the engagement of microglia through the Fc fragment, providing critical insights for optimizing anti-amyloid therapies in Alzheimer’s disease."
New immune process identified that may alleviate Alzheimer's disease (original news release)
The Alzheimer’s therapeutic Lecanemab attenuates Aβ pathology by inducing an amyloid-clearing program in microglia (open access)
Fig. 1: Lecanemab drives strong transcriptional changes in human microglia associated with Aβ plaques.
Fig. 2: Lecanemab alleviates Aβ pathology by triggering effector functions in the microglia.
No comments:
Post a Comment