Abstract
Alzheimer´s disease (AD) is characterized by progressive dementia, initially presenting olfactory dysfunction. Despite the olfactory bulb (OB) is the first central structure of the olfactory pathway, we lack a complete molecular characterization of the transcriptional events that occurs in this olfactory area during AD progression. To address this gap in knowledge, we have assessed the genome-wide expression in postmortem OBs from subjects with varying degree of AD pathology. A stage-dependent deregulation of specific pathways was observed, revealing transmembrane transport, and neuroinflammation as part of the functional modules that are disrupted across AD grading. Potential drivers of neurodegeneration predicted by network-driven transcriptomics were monitored across different types of dementia, including progressive supranuclear palsy (PSP), mixed dementia, and frontotemporal lobar degeneration (FTLD). Epidermal growth factor receptor (EGFR) expression was significantly increased in the OB of AD and mixed dementia subjects. Moreover, a significant increment in the activation of signal transducer and activator of transcription 3 (STAT3) was exclusively detected in advanced AD stages, whereas total STAT3 levels were specifically overexpressed in mixed dementia. Furthermore, transcription factors deregulated in the OB of mixed dementia subjects such as cAMP Responsive Element Binding Protein 1 (CREB1) and AP-1 Transcription Factor Subunit (c-Jun) were not differentially modulated at olfactory level across AD grading. On the other hand, olfactory expression of this signal transducer panel was unchanged in PSP and FTLD subjects. Taken together, this study unveils cross-disease similarities and differences for specific signal transducers, providing mechanistic clues to the intriguing divergence of AD pathology across proteinopathies.
Highlights
Olfactory involvement may appear in healthy non-demented elderly subjects [1], olfactory dysfunction is present in up to 90% of Alzheimers disease (AD) patients [2]
We have analyzed the progressive modulation of the olfactory bulb (OB) transcriptome across neuropathological stages of AD, in order to increase our knowledge about the pathophysiological mechanisms that are disturbed during the AD neurodegeneration in the OB. 249 differential genes were detected between controls and AD-related phenotypes, pinpointing specific pathways, gene interaction networks, and potential novel therapeutic targets that are modulated in specific AD stages
Gene expression profiling of postmortem tissue has greatly increased our knowledge about the pathophysiological mechanisms that occur in affected brain structures during AD progression [12]
Summary
Olfactory involvement may appear in healthy non-demented elderly subjects [1], olfactory dysfunction is present in up to 90% of AD patients [2]. From a neuropathological point of view, olfactory centres are involved in early Braak stages [6], and OB pathology correlates with cortical AD pathology [7,8,9]. In view of these data, an in depth biochemical characterization of the neurodegeneration that occurs in the OB is mandatory as a first step for understanding early smell impairment in AD. We consider that deciphering the progressive transcriptome-wide alterations that occurs in the OB derived from human AD cases with different Braak staging, might help develop early diagnosis and identify potential therapeutic targets for AD. The OB transcriptome exploration in parallel with a cross-disease analysis including different proteinopathies, has revealed distinct modulation of specific signal transducers, providing new avenues of research into the role of olfactory signaling across different types of dementias
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