Monomeric C-reactive protein induces the cellular pathology of Alzheimer's disease.

INTRODUCTION

Human study shows that elevated C-reactive protein (CRP) in blood impacts apolipoprotein E () ε4, but not ε3 or ε2, genotype to increase the risk of Alzheimer's disease (AD). However, whether CRP is directly involved in cellular AD pathogenesis and in which type of neuronal cells of ε4 carriers are unknown.

METHODS

We aimed to use different primary neuronal cells and investigate if CRP induces cellular AD pathology depending on genotypes. Here the different primary neuronal cells from the different genotype knock-in mice cortex were isolated and used.

RESULTS

Monomeric CRP (mCRP) increased amyloid beta production and, in parallel, induced tau phosphorylation in addition to their related proteins in the primary neurons in a pattern of ε4 >  ε3 >  ε2 in a dose- and time-dependent manner. Consistently, mCRP induced the staining of other neurodegenerative biomarkers, including Fluoro-Jade B stain (FjB), TUNEL and Cleaved Caspase-3, in primary neurons in a similar pattern of ε4 >  ε3 >  ε2. In contrast, pentameric CRP (pCRP) had a tendency to induce cellular AD pathology but did not reach statistical significance. On the other hand, it is intriguing that regardless of genotype, mCRP did not influence the expressions of Iba-1 and CD68 in primary microglia or the expression of glial fibrillary acidic protein in primary astrocytes, and additionally mCRP did not affect the secretions of interleukin (IL)-1α, IL-1β, and tumor necrosis factor α from these cells.

DISCUSSION

This is the first report to demonstrate that mCRP directly induces cellular AD pathogenesis in neurons in an genotype-dependent pattern, suggesting that mCRP plays a role as a mediator involved in the ε4-related pathway for AD during chronic inflammation.

HIGHLIGHTS

Pentameric C-reactive protein (pCRP) can be dissociated irreversibly to form free subunits or monomeric CRP (mCRP) during and after the acute phase.mCRP increased amyloid beta production in the primary neurons in a pattern of apolipoprotein E () ε4 >  ε3 >  ε2 in a dose-dependent manner.mCRP induced the expression of phosphorylated tau in the primary neurons in a pattern of ε4 >  ε3 >  ε2 in a dose- and time-dependent manner.mCRP plays an important mediator role in the ε4-related pathway of Alzheimer's disease risk.