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

Amyloid-β (Aβ) accumulation is a hallmark of Alzheimer's disease. Cerebral Aβ deposition is attenuated by a functional glymphatic system, in which perivascular entry of cerebrospinal fluid (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 Aβ pathology, AppNL-F and AppNL-G-F. AppNL-F mice showed reductions in glymphatic influx and clearance at 6 months, preceding substantial Aβ plaque deposition. The decrease in glymphatic function in AppNL-F mice correlated with a loss of PBMs and altered marker expression. Acute administration of Aβ 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 due to an enhanced Aβ phagocytic capacity in PBMs. Four weeks of systemic anti-Aβ antibody treatment efficiently reduced Aβ 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 Aβ plaque load but is closely linked to pre-plaque Aβ-induced loss of PBMs. Preservation of PBM abundance and their normal marker expression may be important for maintaining glymphatic function and mitigating early progression of Alzheimer's disease.