Translational potential of mouse CSF biomarkers in Alzheimer’s disease: Association of CSF neurogranin with tau, NFL and amyloid pathology in APP knock‐in mouse models

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is characterized by early and progressive synaptic dysfunction and loss that are closely related to cognitive impairment in AD patients. Neurogranin (Ng) has emerged as a potential marker of synaptic dysfunction, with cerebrospinal fluid (CSF) levels specifically increased in AD. In order to investigate the translational potential of CSF Ng, the present study investigated its alterations and relationship to AD‐related pathology (Aβ42, tau and neurofilament light; NFL) in both CSF and brain tissue of novel App knock‐in mouse models.MethodsCSF and brain tissue were sampled from 12‐months old wild type (WT), AppNL‐F/NL‐F and AppNL‐G‐F/NL‐G‐F mice. CSF and brain (cortex and hippocampus) Ng, Aβ42, t‐tau and NFL protein levels were analyzed using new ultra sensitive digital enzyme‐linked immunosorbent assays on the Simoa platform. Differences in expression of Ng in the brain tissue and its relation to amyloid plaques in App knock‐in mice were investigated by immunohistochemistry (IHC).ResultsCSF Ng, t‐tau and NFL levels were significantly increased in App knock‐in compared to WT mice (p < 0.05). CSF Ng negatively correlated with Ng levels in the cortex and Aβ42 levels in the CSF and positively correlated with CSF t‐tau and NFL levels (p < 0.05). Loss of neurogranin in the dendrites of hippocampal CA1 region of App knock‐in mice was closely associated with the localization of Aβ plaques in double IHC stainings.ConclusionsApp knock‐in mice exhibit synaptic degeneration that is associated with AD neuropathology and remarkably comparable to findings from clinical studies. CSF Ng is potential translational marker of synaptic degeneration in AD.