Reduced CSF Aβ42 and Aβ42/Aβ40 ratio during early cerebral amyloid deposition in the AppNL‐F knock‐in mouse model of Alzheimer’s disease

Abstract

AbstractBackgroundThe concentration of Aβ42 in cerebrospinal fluid (CSF) is decreased at least a decade before cognitive symptoms caused by Alzheimer’s disease (AD) manifest. This drop in concentration has been suggested to occur before abnormal levels of fibrillar Aβ in the brain are reached, but the underlying cause is not well understood. The present study aims to explore the translational potential of the App NL‐F knock‐in mouse model, and compare it to transgenic App‐overexpressing 3xTg mice, for investigation of the early events in Aβ pathology that associates with reduced CSF Aβ42 in preclinical AD.MethodCSF and brain tissue was collected from 3‐18 months old App NL‐F knock‐in mice (n=56) and 3‐24 months old 3xTg mice (n=74). CSF Aβ40 and Aβ42 concentrations were measured using Single Molecule Array (Simoa) technology and immunohistochemistry was performed on brain sections for detection of cerebral Aβ deposition.ResultIn App NL‐F knock‐in mice, CSF Aβ40 remained unchanged while CSF Aβ42 and Aβ42/Aβ40 ratio were reduced from 12 months of age after which a plateau was reached (Fig.1). The initial reduction coincided with early deposition of cortical Aβ42 in the brain that gradually increased with age (Fig.2). Accordingly, in the whole study population, CSF Aβ42 and Aβ42/Aβ40 ratio showed a moderate negative hyperbolic association with cortical Aβ42 load (Fig.3). In comparison, increased CSF Aβ40 and Aβ42 was observed in 3xTg mice prior to Aβ plaque deposition, although the Aβ42/Aβ40 ratio remained stable. These changes coincided with the accumulation of cerebral intracellular Aβ. Once Aβ plaques started to deposit in the brain from 12 months of age, a subsequent reduction of CSF Aβ42 and Aβ42/Aβ40 was observed (Fig.4).ConclusionIn line with clinical findings, CSF Aβ42 and Aβ42/Aβ40 ratio are reduced in App NL‐F knock‐in mice and seem to reflect pathological processes that occur slightly before deposition of amyloid in the brain is widespread. This reduction quickly starts to stabilize towards a plateau, although accumulation of cerebral amyloid steadily continues to increase. In contrast to 3xTg mice, no initial increase in CSF Aβ40 and Aβ42 was observed and further studies are needed to elucidate these differences and their translational implication.