CSF levels of the BACE1 substrate Neuregulin1 correlate with cognition and synaptic biomarkers in Alzheimer’s disease

Background The presynaptic protein Neuregulin1 (Nrg1) is cleaved by BACE 1 like amyloid precursor protein (APP), can activate post‐synaptic ErbB4 receptors and has been linked to schizophrenia. The couple Nrg1/ErbB4 is neuroprotective, can trigger synaptogenesis and plasticity and increases the expression of NMDA and GABA receptors. In addition this couple can also induce neuroinflammation and can reduce memory formation. In Alzheimer’s disease (AD) Nrg1 accumulates in neuritic plaques. It is therefore difficult to determine if Nrg1 has beneficial and/or detrimental effects in AD. BACE 1 levels are increased in AD brains and CSF, but no study has assessed CSF Nrg1 levels in AD and MCI‐ AD patients. Method This is a retrospective study, including 172 patients suffering from AD dementias (56), MCI‐ AD (21), non‐AD MCI (32), non‐AD dementias (36) and neurological controls (27). All patients had neurological exams, MRI and neuropsychological evaluations. After written informed consent and using the ELISA method, the CSFs of all patients were evaluated for Aβ1‐42, Aβ1‐40, tau, ptau, BACE1, neurogranin, SNAP25, SNAP25 aa40, synaptotagmin and Nrg1. Result Levels of Nrg1 were significantly increased in the CSF of AD and MCI‐AD patients compared to non‐AD MCI, non‐AD dementias and neurological controls. In addition, Nrg1 levels positively correlated with tau, ptau, Aβ 1‐40, all synaptic biomarkers and BACE1 levels and negatively with MMSE and Frontal Battery ( BREF) scores. Conclusion APP and Nrg1 are both cleaved by BACE 1 at synaptic levels. Aβ toxicity induces synaptic degradation with increased CSF levels of synaptic biomarkers and Nrg1. Reduced brain Nrg1 levels may reduce neuroptotection. Nrg1 is a new biomarker reflecting BACE1 activity and Aβ‐ induced neurodegeneration and can be correlated with the cognitive status in MCI‐AD and AD patients.