Cerebrospinal fluid neurogranin in an inducible mouse model of neurodegeneration: A translatable marker of synaptic degeneration

Kina Höglund,Nathalie Schussler,Hlin Kvartsberg,Una Smailovic,Gunnar Brinkmalm,Victor Liman,Bruno Becker,Henrik Zetterberg,Angel Cedazo-Minguez,Shorena Janelidze,Isabel A Lefevre,Stéphanie Eyquem,Oskar Hansson,Kaj Blennow

doi:10.1016/j.nbd.2019.104645

Abstract

Synapse impairment is thought to be an early event in Alzheimer's disease (AD); dysfunction and loss of synapses are linked to cognitive symptoms that precede neuronal loss and neurodegeneration. Neurogranin (Ng) is a somatodendritic protein that has been shown to be reduced in brain tissue but increased in the cerebrospinal fluid (CSF) of AD patients compared to age-matched controls. High levels of CSF Ng have been shown to reflect a more rapid AD progression. To gauge the translational value of Ng as a biomarker, we developed a new, highly sensitive, digital enzyme-linked immunosorbent assay (ELISA) on the Simoa platform to measure Ng in both mouse and human CSF. We investigated and confirmed that Ng levels are increased in the CSF of patients with AD compared to controls. In addition, we explored how Ng is altered in the brain and CSF of transgenic mice that display progressive neuronal loss and synaptic degeneration following the induction of p25 overexpression. In this model, we found that Ng levels increased in CSF when neurodegeneration was induced, peaking after 2 weeks, while they decreased in brain. Our data suggest that CSF Ng is a biomarker of synaptic degeneration with translational value.

Highlights

Alzheimer's disease (AD) is a progressive neurodegenerative disease with key pathological hallmarks including amyloid plaques, neurofibrillary tangles and neurodegeneration (Scheltens et al, 2016)
We recently described increased cerebrospinal fluid (CSF) levels of neurofilament light (NFL) upon neurodegeneration (Brureau et al, 2017) and in prior studies we documented substantial synaptic degeneration as demonstrated by reduced levels of the post-synaptic protein PSD-95 in the hippocampus; in contrast, no decrease in hippocampal PSD-95 levels was found in 8 month-old APP/PS1 (Thy1.APPmutxPS1M146L, the mouse model described in Blanchard et al (Blanchard et al, 2003)), and 9 month-old ThyTau22 (Schindowski et al, 2006) mice compared to wild-type mice
We present a successfully developed and pre-validated ultrasensitive assay for the quantification of Ng in both mouse and human CSF and we first confirmed that CSF levels of Ng are significantly increased in patients with AD compared to controls, as has been reported previously (Kester et al, 2015; Kvartsberg et al, 2014; Kvartsberg et al, 2015; Thorsell et al, 2010; Wellington et al, 2016)

Summary

Introduction

Alzheimer's disease (AD) is a progressive neurodegenerative disease with key pathological hallmarks including amyloid plaques, neurofibrillary tangles and neurodegeneration (Scheltens et al, 2016). The degree of cognitive impairment has been found to be more closely associated with synaptic loss compared to amyloid plaques or neurofibrillary tangle content (Masliah et al, 2001; Scheff et al, 2007; Blennow et al, 1996; Davies et al, 1987; Sze et al, 1997), in certain areas of the brain, such as the hippocampus (Scheff et al, 2007; Scheff et al, 2006). Neurogranin (Ng) is a protein expressed in neurons of the amygdala, hippocampus, cerebral cortex and other associative cortical areas (Bogdanovic et al, 2002). Neurogranin is present in the Neurobiology of Disease 134 (2020) 104645 somatodendritic compartment and can be translocated, upon stimulation, together with calmodulin (CaM) at the dendritic spines where it can sequester CaM, thereby regulating its local availability and controlling the spatiotemporal patterns of Ca2+/CaM dependent signaling (Diez-Guerra, 2010; Huang and Huang, 2011; Huang et al, 2011; Petersen and Gerges, 2015)

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