Abstract
Olfactory dysfunction is among the earliest features of Alzheimer’s disease (AD). Although neuropathological abnormalities have been detected in the olfactory bulb (OB), little is known about its dynamic biology. Here, OB- proteome analysis showed a stage-dependent synaptic proteostasis impairment during AD evolution. In addition to progressive modulation of tau and amyloid precursor protein (APP) interactomes, network-driven proteomics revealed an early disruption of upstream and downstream p38 MAPK pathway and a subsequent impairment of Phosphoinositide-dependent protein kinase 1 (PDK1)/Protein kinase C (PKC) signaling axis in the OB from AD subjects. Moreover, a mitochondrial imbalance was evidenced by a depletion of Prohibitin-2 (Phb2) levels and a specific decrease in the phosphorylated isoforms of Phb1 in intermediate and advanced AD stages. Interestingly, olfactory Phb subunits were also deregulated across different types of dementia. Phb2 showed a specific up-regulation in mixed dementia, while Phb1 isoforms were down-regulated in frontotemporal lobar degeneration (FTLD). However, no differences were observed in the olfactory expression of Phb subunits in progressive supranuclear palsy (PSP). To sum up, our data reflect, in part, the missing links in the biochemical understanding of olfactory dysfunction in AD, unveiling Phb complex as a differential driver of neurodegeneration at olfactory level.
Highlights
Alzheimer’s disease (AD) is the most common form of senile dementia[1]
To determine the olfactory bulb (OB) site-specific proteomic signature during AD progression, a label-free mass spectrometry (MS)-based approach was performed on OB tissue derived from AD subjects with different grading and controls with no known neurological history (Table 1)
Our analysis revealed that 110 olfactory proteins are differentially expressed in early AD stages, increasing the proteome alterations as the disease progresses (125, and 158 differential proteins in intermediate and advanced stages respectively) (Fig. 1b)
Summary
Alzheimer’s disease (AD) is the most common form of senile dementia[1]. In general, two subgroups are recognized, a familial early-onset form, and a sporadic late-onset form, albeit 95% of the patients develop sporadic AD2. Together with typical symptoms such as memory loss and behavioral disorders, AD patients present olfactory dysfunction in 90% of the cases[3] This deficit occurs at early stages of the disease and it is considered a premotor sign of neurodegeneration[3, 4]. Taking into account the cellular complexity and protein heterogeneity present in the OB8, 9, proteome-wide analysis based on high-resolution MS10 has become an attractive technology to characterize and quantify the OB proteome in different biological contexts[11] This unbiased technology has greatly enhanced the ability to characterize novel pathways in brain areas associated with AD12, 13, few studies have examined the proteome profiling of the early-affected OB region with the aim to investigate incipient neurodegenerative changes in AD phenotypes. A cross-disease study pointed out that Phb subunits are differentially modulated in the OB across AD-related co-pathologies, providing mechanistic clues to the intriguing divergence of AD pathology across different types of dementias
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