The AppNL‐F mouse model of Alzheimer’s Disease demonstrates reduced serum Aß42 levels and Aß42/Aß40 ratio, changes that correlate with CSF Aß levels and cerebral Aß42 plaque load

Abstract

AbstractBackgroundRecent development of novel assays has made it possible to reliably measure proteins for diagnosis of Alzheimer’s disease (AD) in blood in addition to cerebrospinal fluid (CSF). Previous studies have shown that blood and CSF Aß40 and Aß42 levels correlate in AD patients, and other studies have demonstrated that a reduced plasma Aß42/Aß40 ratio inversely correlates with amyloid burden in the brain (determined by PET). However, more studies are needed to fully understand how these Aß changes in blood correlate with CSF Aß as well as the cerebral Aß plaque load. In this current study, we aim to investigate these associations by the use of a novel knock‐in mouse model, AppNL‐F.MethodSerum, CSF and brain tissue was collected from 3‐18 months old App NL‐F knock‐in mice. Levels of serum and CSF Aß40 and Aß42 were analyzed using Simoa Technology (Quantrix). Mouse brain sections were immunostained against Aß42 to determine the cerebral Aß42 plaque load.ResultIn serum from our AppNL‐F mouse model, we found increased levels of Aß40, decreased levels of Aß42 as well as a decreased Aß42/Aß40 ratio with increasing age, particularly after 12 months of age, which was similar in time to the changes observed in CSF. These alterations in serum Aß42 levels and Aß42/Aß40 ratio were associated with the increase of cerebral Aß42 plaque load (Rs ‐0.50 and ‐0.51, respectively), which were lower compared to the associations between CSF Aß42 and Aß42/Aß40 ratio with Aß42 plaque load (‐0.71 and ‐0.70, respectively).ConclusionOur results from the AppNL‐F knock‐in model, show that decreased serum Aß42 and Aß42/Aß40 ratio are mirroring both the decreased Aß42 and Aß42/Aß40 ratio in CSF as well as correlate with increasing cerebral Aß plaque load. These findings indicate that Aß changes in serum and CSF in the AppNL‐F mouse model mirror Aß alterations seen in preclinical AD. Furthermore, these results suggest that changes in Aß42 and Aß42/Aß40 ratio occur simultaneously in serum and CSF and well in concurrent with the deposition of Aß in the brain.