Abstract

Ras/ERK, /p-38, /JNK and PI3K/AKT pathways may mediate amyloid-β-peptide toxicity, neuron death and cognitive decline, modulating oxidative stress and inflammation in AD. Although it is a neurodegenerative disorder, AD affects different systemic molecular mechanisms that are present in patients’ peripheral tissues, too. We investigated possible MAPK and PI3K-AKT alterations in fibroblast primary cultures from sporadic AD, MCI and control subjects, testing these molecular pathways as possible AD-related trait markers.

By western blot and phospho-Elisa, we evaluated their epigenetic status and some of their downstream pathways that might be involved in preclinical and early AD stages: the alpha-APP-levels, as a marker of the alpha-secretase activity, the expression of Bax, as an apoptosis and mTOR-autophagy regulator and the phospho-p70S6K status, that modulates protein synthesis, Tau hyper-phosphorylation and mTOR-cell signaling.

While the expression of phospho-ERK1/2 decreased in fibroblasts from mild/moderate AD compared to severe patients’ and controls’ cells, it did not shown difference in fibroblasts from seven sporadic Parkinson Disease patients compared to HC. Moreover, phospho-ERK1/2 expression and AD severity correlated and including MCI-converter patients to AD cases, this statistical significance was further confirmed. The expression of phospho-AKT also increased in the cells of severe AD patients compared to the fibroblasts of patients with mild/moderate AD, MCI and control subjects and it correlated with the disease severity, too. Phospho-p38- and phospho-JNK-SAP Kinases as well as phospho-p70S6K and Bax increased in cells from AD patients but did not correlate with disease severity, while alpha- APP levels decreased in patients’ cells and it only correlated to phospho-ERK1/2 levels in control fibroblasts, indicating the ERK involvement in the physiological metabolism of APP.

Then ERK1/2 and AKT pathways could be suitable to check the disease molecular mechanisms in these peripheral cells from the disease prodromal stage, in particular, ERK-modulation might help to discriminate converter and nonconverter MCI. Furthermore, since fibroblasts show molecular dysfunctions similar to those observed in autopsy brains, these cells might also be useful peripheral targets to investigate and modulate Aβ-related APP metabolism, Tau hyper-phosphorylation and mTOR-cell signaling, preventing the AD progression.

Keywords: ERK and AKT; MMSE; MCI-Converter; Alpha-APP; P70S6Kinase; Tau synthesis; Apoptosis; mTOR-pathway; Personalized drugs