Olfactory bulb proteome dynamics during the progression of sporadic Alzheimer's disease: identification of common and distinct olfactory targets across Alzheimer-related co-pathologies

Abstract

Olfactory dysfunction is present in up to 90% of Alzheimer's disease (AD) patients. Although deposition of hyperphosphorylated tau and β-amyloid substrates are present in olfactory areas, the molecular mechanisms associated with decreased smell function are not completely understood. We have applied mass spectrometry-based quantitative proteomics to probe additional molecular disturbances in postmortem olfactory bulbs (OB) dissected from AD cases respect to neurologically intact controls (n=20, mean age 82.1 years). Relative proteome abundance measurements have revealed protein interaction networks progressively disturbed across AD stages suggesting an early imbalance in splicing factors, subsequent interrupted cycling of neurotransmitters, alteration in toxic and protective mechanisms of β-amyloid, and finally, a mitochondrial dysfunction together with disturbance in neuron-neuron adhesion. We also present novel molecular findings in the OB in an autopsy cohort composed by Lewy body disease (LBD), frontotemporal lobar degeneration (FTLD), mixed dementia, and progressive supranuclear palsy (PSP) cases (n = 41, mean age 79.7 years). Olfactory mediators deregulated during the progression of AD such as Visinin-like protein 1, RUFY3 protein, and Copine 6 were also differentially modulated in the OB in LBD, FTLD, and mixed dementia. Only Dipeptidyl aminopeptidase-like protein 6 showed a specific down-regulation in AD. However, no differences were observed in the olfactory expression of this protein panel in PSP subjects. This study demonstrates an olfactory progressive proteome modulation in AD, unveiling cross-disease similarities and differences especially for specific proteins involved in dendritic and axonic distributions that occur in the OB during the neurodegenerative process.

An integrated proteomics approach shows synaptic plasticity changes in an APP/PS1 Alzheimer's mouse model

“…This suggests that an aberrant expression level and/or activity of 14-3-3 proteins in the olfactory bulb of both AD patients and APP/PS1 mice may link to NFT-like structures. In agreement with this study, Zelaya et al noted a decrease in 14-3-3 proteins in the olfactory bulb of human post-mortem AD cases using proteomics [35]. They found an impressing number of deregulated proteins (231) that are involved in dendritic morphogenesis, neuronal injury and axonic distribution.…”

Proteomic differences in amyloid plaques in rapidly progressive and sporadic Alzheimer’s disease

“…First, the significantly altered proteins in rpAD plaques were compared to our database of AD associated proteins identified in previous proteomic studies[1, 2, 4, 11, 13, 14, 22, 31–33, 36, 37, 43, 45, 50, 54, 55, 66, 77, 78, 82, 89, 90, 96]. In this database we annotated proteins as up-regulated in AD, down-regulated in AD and proteins that are enriched in plaques or tangles (Supplementary Table 1).…”

“…This database combined the results from studies that identified proteins in neurofibrillary tangles[50, 66, 82], proteins enriched in plaques[32, 43], proteins that had significantly altered expression in various regions and/or fractions of AD brains in comparison to control brains and proteins that contained the keyword “Alzheimer” in the Uniprot human database[1, 2, 4, 11, 13, 14, 22, 31–33, 36, 37, 45, 54, 55, 77, 78, 89, 90, 96]. Protein groups identified in rpAD and sAD plaques were screened against this database to determine how many of the proteins identified in this study have been previously associated with AD pathology.…”

Proteomics of neurodegenerative diseases: analysis of human post‐mortem brain

“…; Zelaya et al . ), and studies involving animal and cellular models, have largely been covered by previous reviews (Fasano et al . ; Moya‐Alvarado et al .…”