Abstract
The olfactory bulb (OB) is the first processing station in the olfactory pathway. Despite smell impairment, which is considered an early event in Alzheimer’s disease (AD), little is known about the initial molecular disturbances that accompany the AD development at olfactory level. We have interrogated the time-dependent OB molecular landscape in Tg2576 AD mice prior to the appearance of neuropathological amyloid plaques (2-, and 6-month-old), using combinatorial omics analysis. The metabolic modulation induced by overproduction of human mutated amyloid precursor protein (APP) clearly differs between both time points. Besides the progressive perturbation of the APP interactome, functional network analysis unveiled an inverse regulation of downstream extracellular signal-regulated kinase (ERK1/2), and p38 mitogen-activated protein kinase (MAPK) routes in 2-month-old Tg2576 mice with respect to wild-type (WT) mice. In contrast, Akt and MAPK kinase 4 (SEK1)/ stress-activated protein kinase (SAPK) axis were parallel activated in the OB of 6-months-old-Tg2576 mice. Furthermore, a survival kinome profiling performed during the aging process (2-, 6-, and 18-month-old) revealed that olfactory APP overexpression leads to changes in the activation dynamics of protein kinase A (PKA), and SEK1/MKK4-SAPK/JNK between 6 and 18 months of age, when memory deficits appear and AD pathology is well established in transgenic mice. Interestingly, both olfactory pathways were differentially activated in a stage-dependent manner in human sporadic AD subjects with different neuropathological grading. Taken together, our data reflect the early impact of mutated APP on the OB molecular homeostasis, highlighting the progressive modulation of specific signaling pathways during the olfactory amyloidogenic pathology.
Highlights
Together with typical symptoms, such as memory loss and behavioral disorders, Alzheimer’s disease (AD) patients present olfactory dysfunction in 90% of the cases (Attems et al, 2014; Daulatzai, 2015)
With respect to transcriptome-wide analysis, 187 protein-coding genes were differentially regulated in the olfactory bulb (OB) of 2-month-old Tg2576 mice (46 down- and 141 up-regulated genes with respect to WT mice), whereas 287 differentially expressed genes were found in 6-monthold Tg2576 OBs (107 down- and 180 up-regulated genes with respect to WT mice; Figure 2B, and Supplementary Table S1)
The expression levels of 31 proteins were found to be significantly different between 2-month-old WT and Tg2576 mice (12 down- and 19 up-regulated proteins with respect to WT mice), and 61 differentially expressed proteins were detected at 6 months of age (26 down- and 35 up-regulated proteins with respect to WT animals; Figures 2B,C, and Supplementary Table S2)
Summary
Together with typical symptoms, such as memory loss and behavioral disorders, Alzheimer’s disease (AD) patients present olfactory dysfunction in 90% of the cases (Attems et al, 2014; Daulatzai, 2015). No animal model recapitulates the entirety of human AD pathology (Sasaguri et al, 2017), some AD transgenic mouse models present olfactory deficits. The presence of APP processing products has been characterized in the OB of 1-month-old Tg2576 mice (Lehman et al, 2003). This progressive Aβ deposition in specific olfactory structures is accompanied by behavioral deficits in odor habituation and discrimination, diminished rate of OB neurogenesis, and an altered volume of the OB granular cell layer in Tg2576 mice (Guérin et al, 2009; Young et al, 2009; Wesson et al, 2010, 2011)
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