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.