An early dysregulation of FAK and MEK/ERK signaling pathways precedes the beta-amyloid deposition in the olfactory bulb of APP/PS1 mouse model of Alzheimer%26apos;s disease

作者：Lachen Montes Mercedes; Gonzalez Morales Andrea; Martinez de Morentin Xabier; Perez Valderrama Estela; Ausin Karina; Victoria Zelaya Maria; Serna Antonio; Aso Ester; Ferrer Isidro; Fernandez Irigoyen Joaquin; Santamaria Enrique

来源：Journal of Proteomics, 2016, 148: 149-158.

DOI：10.1016/j.jprot.2016.07.032

• Alzheimer
• Proteomics
• Olfactory bulb
• Brain
• APP/PS1 model

Olfactory dysfunction is an early event of Alzheimer's disease (AD). However, the mechanisms associated to AD neurodegeneration in olfactory areas are unknown. Here we used double-transgenic amyloid precursor protein/presenilin 1 (APPswe/PS1dE9) mice and label-free quantitative proteomics to analyze early pathological effects on the olfactory bulb (OB) during AD progression. Prior to beta-amyloid plaque formation, 9 modulated proteins were detected on 3-month-old APP/PS1 mice while 16 differential expressed proteins were detected at 6 months, when beta-amyloid plaques appear, indicating a moderate imbalance in cytoskeletal rearrangement, and synaptic plasticity in APP/PS1 OBs. Moreover, beta-amyloid induced an inactivation of focal adhesion kinase (FAK) together with a transient activation of MEK1/2, leading to inactivation of ERK1/2 in 6-months APP/PS1 OBs. In contrast, the analysis of human OBs revealed a late activation of FAK in advanced AD stages, whereas ERK1/2 activation was enhanced across AD staging respect to controls. This survival potential was accompanied by the inhibition of the proapototic factor BAD in the OB across AD phenotypes. Our data contribute to a better understanding of the early molecular mechanisms that are modulated in AD neurodegeneration, highlighting significant differences in the regulation of survival pathways between APP/PS1 mice and sporadic human AD.
Significance: Loss of smell is involved in early stages of Alzheimer's disease (AD), usually preceding classic disease symptoms. However, the mechanisms governing this dysfunction are still poorly understood, losing its potential as a useful tool for clinical diagnosis. Our study characterizes potential AD-associated molecular changes in APP/PS1 mice olfactory bulb (OB) using MS-quantitative proteomics, revealing early cytoskeletal disruption and synaptic plasticity impairment. Moreover, an opposite pattern was found when comparing the activation status of specific survival pathways between APP/PS1 OBs and OBs derived from sAD subjects with different neuropathological grading. Our data reflect, in part, the progressive effect of APP overproduction and A beta accumulation on the OB proteome during AD progression.

• 出版日期2016-10-4