The intact postsynaptic protein neurogranin is reduced in brain tissue from patients with familial and sporadic Alzheimer’s disease

Abstract

Synaptic degeneration and neuronal loss are early events in Alzheimer’s disease (AD), occurring long before symptom onset, thus making synaptic biomarkers relevant for enabling early diagnosis. The postsynaptic protein neurogranin (Ng) is a cerebrospinal fluid (CSF) biomarker for AD, also in the prodromal phase. Here we tested the hypothesis that during AD neurodegeneration, processing of full-length Ng into endogenous peptides in the brain is increased. We characterized Ng in post-mortem brain tissue and investigated the levels of endogenous Ng peptides in relation to full-length protein in brain tissue of patients with sporadic (sAD) and familial Alzheimer’s disease (fAD), healthy controls and individuals who were cognitively unaffected but amyloid-positive (CU-AP) in two different brain regions. Brain tissue from parietal cortex [sAD (n = 10) and age-matched controls (n = 10)] and temporal cortex [sAD (n = 9), fAD (n = 10), CU-AP (n = 13) and controls (n = 9)] were included and all the samples were analyzed by three different methods. Using high-resolution mass spectrometry, 39 endogenous Ng peptides were identified while full-length Ng was found to be modified including disulfide bridges or glutathione. In sAD parietal cortex, the ratio of peptide-to-total full-length Ng was significantly increased for eight endogenous Ng peptides compared to controls. In the temporal cortex, several of the peptide-to-total full-length Ng ratios were increased in both sAD and fAD cases compared to controls and CU-AP. This finding was confirmed by western blot, which mainly detects full-length Ng, and enzyme-linked immunosorbent assay, most likely detecting a mix of peptides and full-length Ng. In addition, Ng was significantly associated with the degree of amyloid and tau pathology. These results suggest that processing of Ng into peptides is increased in AD brain tissue, which may reflect the ongoing synaptic degeneration, and which is also mirrored as increased levels of Ng peptides in CSF.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1910-3) contains supplementary material, which is available to authorized users.

CSF neurogranin as a neuronal damage marker in CJD: a comparative study with AD

“…Recently, the presence of increased neurogranin processing peptides and decreased full-length protein has been reported in AD brain tissue 42 . These observations suggest that neurogranin processing in AD may reflect the synaptic degeneration.…”

Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer's disease

“…The Elecsys ® immunoassays (Roche Diagnostics) were used for the main analysis of CSF Aβ42, Aβ40, T‐tau, and P‐tau (Hansson et al , ). NfL and neurogranin were analyzed as previously described (Mattsson et al , ,b; Hansson et al , ; Kvartsberg et al , ). YKL‐40 concentrations were measured using ELISA kits according to the manufacturer's recommendations (YKL‐40 R&D Systems, Inc., Minneapolis, MN, USA) (Janelidze et al , ).…”

The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease

“…Following the identification of synaptic protein fragments of neurogranin, SNAP-25, and synaptotagmin in CSF [115,116], specific protein biomarkers of synapse degeneration have begun to emerge in recent years. Protein fragments of neurogranin, a dendritic protein involved in LTP, are increased in CSF of patients with AD, and full-length neurogranin is decreased in post-mortem brain tissues [117,118]. Furthermore, encouraging data show that increased neurogranin fragments in CSF correlate with future cognitive decline, brain atrophy, and glucose metabolism, even at early stages of the disease [117,[119][120][121], and that the increase in CSF neurogranin seems to be specific for AD [122,123].…”