Early glymphatic failure in AppNL-F knock-in mice is linked to parenchymal border macrophages loss

Abstract

Amyloid-beta (A beta) accumulation is a hallmark of Alzheimer's disease. Cerebral A beta deposition is attenuated by a functional glymphatic system, in which perivascular entry of CSF and its exchange with interstitial fluid mediate solute clearance. Parenchymal border macrophages (PBMs), positioned along glymphatic pathways, are emerging as important players for glymphatic clearance. However, how glymphatic function and PBMs are affected in App knock-in models of Alzheimer's disease is unknown.In this study, we used two App knock-in mouse models that develop progressive A beta pathology, AppNL-F and AppNL-G-F. AppNL-F mice showed reductions in glymphatic influx and clearance at 6 months, preceding substantial A beta plaque deposition. The decrease in glymphatic function in AppNL-F mice was correlated with a loss of PBMs and altered marker expression. Acute administration of A beta into the CSF decreased the number of PBMs and impaired glymphatic transport in wild-type mice, thus recapitulating the pre-plaque stage. In contrast, the number of PBMs was not reduced in AppNL-G-F mice, possibly owing to an enhanced A beta phagocytic capacity in PBMs. Four weeks of systemic anti-A beta antibody treatment efficiently reduced A beta plaque load and rescued PBMs in some brain regions; however, the treatment did not restore glymphatic function in the AppNL-F model.These findings suggest that glymphatic dysfunction in App knock-in models of Alzheimer's disease is not driven by parenchymal A beta plaque load but is closely linked to pre-plaque A beta-induced loss of PBMs. Preservation of PBM abundance and their normal marker expression might be important for maintaining glymphatic function and mitigating early progression of Alzheimer's disease. Using knock-in mouse models of Alzheimer's disease, Liu et al. show that A beta-induced loss of parenchymal border macrophages disrupts glymphatic function even before amyloid plaques form. Plaque-reducing immunotherapy fails to restore glymphatic function, highlighting macrophage preservation as a promising therapeutic target.