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.