Plasma and serum neurofilament-light levels increase in an age- and pathology-dependent manner in the Arctic mouse model of Alzheimer's disease.

Abstract

Alzheimer's disease (AD) is the most prevalent form of dementia of the elderly in the US. No disease-modifying drugs have been approved, indicating a need for novel targets and relevant biomarkers to follow treatment efficacy. Neurofilament-light (NfL) is an intermediate filament protein in neurons that increases in plasma after injury and neurodegeneration, suggesting it may be a biomarker of neurodegeneration before other symptoms are evident. Here, we measured blood NfL levels in the Arctic AD mouse and compared levels to a neuroprotective Arctic model in which C5aR1 was genetically ablated (C5aR1KO) and to levels of a microglial activation marker CD11c and fibrillar plaque load in brain. Blood was collected via cardiac puncture from WT, Arctic, C5aR1KO, and ArcticC5aR1KO at 5, 7, 10, and 13 months of age and processed for plasma or serum isolation. The MSD NfL kit was used to detect NfL. Immunohistochemical detection of CD11c-positive microglia and ThioS-stained plaques were analyzed by Imaris. Comparison of NfL in both WT and Arctic mice demonstrated increased levels in Arctic and WT with increasing age (p=0.02 and 0.01, respectively) and a trend for greater levels in Arctic vs WT at 7 (p=0.1) and 13 (p=0.08) months. In ArcticC5aR1KO mice, there was a 44% reduction in NfL compared to Arctic mice at 7 months. Interestingly, by 10 months, NfL levels in ArcticC5aR1KO plasma was 35% higher than in Arctic mice, suggesting that the protective effect observed at 7 months in the ArcticC5aR1KO mice is superseded by 10 months. Similarly, the increase in CD11c and ThioS levels were lower (44%, 37% respectively) in the hippocampus of ArcticC5aR1KO CONCLUSION: This study demonstrated that NfL modulation can be detected with therapeutic intervention (i.e. C5aR1KO), and that changes in NfL paralleled changes in CD11c-positive microglia and fibrillar plaque load. These data suggest that blood levels of NfL can be used in the Arctic mouse model of AD as a biomarker of age and disease progression, which may serve as a noninvasive tool to measure treatment efficacy.