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REDUCED CSF AΒ42 AND AΒ42/AΒ40 RATIO DURING EARLY CEREBRAL AMYLOID DEPOSITION IN THE APP NL-F KNOCK-IN MOUSE MODEL OF ALZHEIMER’S DISEASE
Abstract
Aims
The 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 a novel App knock-in mouse model for investigation of the early events in Aβ pathology that associates with reduced CSF Aβ42 in preclinical AD.
Methods
CSF and brain tissue was collected from 3-18 months old AppNL-F knock-in mice. CSF Aβ40 and Aβ42 concentrations were measured using Single Molecule Array (Simoa) technology. Immunohistochemistry and Thioflavin S staining was performed on brain sections for detection of Aβ42 and amyloid fibrils, respectively.
Results
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 Aβ42 and fibrillar plaques in the brain that gradually increased with age (Fig.2).
Conclusions
CSF Aβ42 and Aβ42/Aβ40 ratio are reduced in AppNL-F knock-in mice and seems to reflect pathological processes that occur slightly before deposition of amyloid in the brain is widespread. This reduction quickly reaches a plateau, although accumulation of cerebral amyloid steadily continues to increase. These results are in good agreement with clinical findings, emphasizing the use of AppNL-F knock-in mice to further investigate the underlying cause of the change in these CSF biomarkers in preclinical AD.