Synaptic markers of cognitive decline in neurodegenerative diseases: a proteomic approach

Abstract

See Attems and Jellinger (doi:10.1093/brain/awx360) for a scientific commentary on this article.Cognitive changes occurring throughout the pathogenesis of neurodegenerative diseases are directly linked to synaptic loss. We used in-depth proteomics to compare 32 post-mortem human brains in the prefrontal cortex of prospectively followed patients with Alzheimer's disease, Parkinson's disease with dementia, dementia with Lewy bodies and older adults without dementia. In total, we identified 10 325 proteins, 851 of which were synaptic proteins. Levels of 25 synaptic proteins were significantly altered in the various dementia groups. Significant loss of SNAP47, GAP43, SYBU (syntabulin), LRFN2, SV2C, SYT2 (synaptotagmin 2), GRIA3 and GRIA4 were further validated on a larger cohort comprised of 92 brain samples using ELISA or western blot. Cognitive impairment before death and rate of cognitive decline significantly correlated with loss of SNAP47, SYBU, LRFN2, SV2C and GRIA3 proteins. Besides differentiating Parkinson's disease dementia, dementia with Lewy bodies, and Alzheimer's disease from controls with high sensitivity and specificity, synaptic proteins also reliably discriminated Parkinson's disease dementia from Alzheimer's disease patients. Our results suggest that these particular synaptic proteins have an important predictive and discriminative molecular fingerprint in neurodegenerative diseases and could be a potential target for early disease intervention.

Large-scale proteomic analysis of human prefrontal cortex identifies proteins associated with cognitive trajectory in advanced age

“…Consistently, in both Banner and BLSA, we found that lower abundance of SNAP25 was associated with faster cognitive decline. Furthermore, Bereczki and colleagues performed a comprehensive study of 851 synaptic proteins in neurodegenerative diseases and cognitive decline 51 . They found that reduced levels of synaptic proteins SNAP47, SYBU, LRFN2, SV2C, and GRIA3 were associated with cognitive impairment and faster cognitive decline 51 .…”

“…Furthermore, Bereczki and colleagues performed a comprehensive study of 851 synaptic proteins in neurodegenerative diseases and cognitive decline 51 . They found that reduced levels of synaptic proteins SNAP47, SYBU, LRFN2, SV2C, and GRIA3 were associated with cognitive impairment and faster cognitive decline 51 . Among these proteins, only GRIA3 was detected in our datasets and had lower abundance in faster cognitive decline in both Banner and BLSA, consistent with Bereczki and colleagues' finding.…”

Cerebrospinal Fluid Levels of Neurogranin in Parkinsonian Disorders

“…CSF Ng levels have been extensively investigated in Alzheimer's disease (AD), where they are increased compared to controls, increased in amyloid‐beta (Aβ) + mild cognitive impairment (MCI), and linked to cognitive decline and progression from MCI to AD dementia . A recent postmortem, human brain proteome study on patiens with and without dementia found that synaptic proteins, but not any individual protein, could differentiate PD with dementia (PDD) and dementia with Lewy bodies (DLB) from controls and AD and that cognitive impairment and decline in life correlated with loss of synaptic proteins …”

“…4,6-8,10,11 A recent postmortem, human brain proteome study on patiens with and without dementia found that synaptic proteins, but not any individual protein, could differentiate PD with dementia (PDD) and dementia with Lewy bodies (DLB) from controls and AD and that cognitive impairment and decline in life correlated with loss of synaptic proteins. 12 Few studies have examined CSF Ng in PD, finding unchanged or decreased levels of Ng compared to controls. 5,9,13 Even scarcer are studies on Ng and cognitive decline or motor dysfunction, and results are conflicting.…”

Identification of conserved proteomic networks in neurodegenerative dementia

“…Similarly, synaptic loss is a common theme across all neurodegenerative disease, but genetic enrichment in specific synaptic modules is not observed universally. The downregulated C1 module was dysregulated exclusively in neurodegenerative dementia cases (AD, FTD-TDP), and not other neurodegenerative conditions suggesting that this module may contribute to shared pathogenic pathways related to cerebral cortical dysfunction (Bereczki et al, 2018;Bigio et al, 2001;Clare et al, 2010;Hassan et al, 2011). Interestingly, this synaptic C1 module was enriched for common genetic variants in PSP, indicating that these synaptic variants may be causal drivers of PSP, but not AD.…”