Neuronal ER-Signalosome Proteins as Early Biomarkers in Prodromal Alzheimer's Disease Independent of Amyloid-β Production and Tau Phosphorylation

Abstract

There exists considerable interest to unveil preclinical period and prodromal stages of Alzheimer's disease (AD). The mild cognitive impairment (MCI) is characterized by significant memory and/or other cognitive domains impairments, and is often considered the prodromal phase of AD. The cerebrospinal fluid (CSF) levels of β-amyloid (βA), total tau (t-tau), and phosphorylated tau (p-tau) have been used as biomarkers of AD albeit their significance as indicators during early stages of AD remains far from accurate. The new biomarkers are being intensively sought as to allow identification of pathological processes underlying early stages of AD. Fifty-three participants (75.4 ± 8.3 years) were classified in three groups as cognitively normal healthy controls (HC), MCI, and subjective memory complaints (SMC). The subjects were subjected to a battery of neurocognitive tests and underwent lumbar puncture for CSF extraction. The CSF levels of estrogen-receptor (ER)-signalosome proteins, βA, t-tau and p-tau, were submitted to univariate, bivariate, and multivariate statistical analyses. We have found that the components of the ER-signalosome, namely, caveolin-1, flotilin-1, and estrogen receptor alpha (ERα), insulin growth factor-1 receptor β (IGF1Rβ), prion protein (PrP), and plasmalemmal voltage dependent anion channel 1 (VDAC) could be detected in the CSF from all subjects of the HC, MCI, and SMC groups. The six proteins appeared elevated in MCI and slightly increased in SMC subjects compared to HC, suggesting that signalosome proteins undergo very early modifications in nerve cells. Using a multivariate approach, we have found that the combination of ERα, IGF-1Rβ, and VDAC are the main determinants of group segregation with resolution enough to predict the MCI stage. The analyses of bivariate relationships indicated that collinearity of ER-signalosome proteins vary depending on the stage, with some pairs displaying opposed relationships between HC and MCI groups, and the SMC stage showing either no relationships or behaviors similar to either HC or MCI stages. The multinomial logistic regression models of changes in ER-signalosome proteins provide reliable predictive criteria, particularly for the MCI. Notably, most of the statistical analyses revealed no significant relationships or interactions with classical AD biomarkers at either disease stage. Finally, the multivariate functions were highly correlated with outcomes from neurocognitive tests for episodic memory. These results demonstrate that alterations in ER-signalosome might provide useful diagnostic information on preclinical stages of AD, independently from classical biomarkers.

Compensatory Mechanisms in Early Alzheimer’s Disease and Clinical Setting: The Need for Novel Neuropsychological Strategies

“…Bivariate relationships (depicted as dotted lines, along with correlation coefficient r ) differed depending on the p-tau range of concentrations (<50, 50–80, and > 80 pg/ml). B) Bivariate plot of In-Out-test punctuations and factor scores for principal component 1 from multivariate analyses of ER-signalosome and scaffolding proteins (modified from reference [ 29 ]). C) Bivariate plot of In-Out-test punctuations and factor scores for principal component 1 from multivariate analyses of trace metals, lipoxidative metabolites, antioxidant/detoxifying enzymes (modified from reference [ 92 ]).…”

“…As these changes do not necessarily lead to AD-type dementia, the question arises of how these alterations may be predictive of a neurodegenerative outcome. We have observed such alterations in neurolipids (docosahexaenoic acid, docosapentaenoic acid), ER-signalosome multiprotein complex (including the estrogen receptor alpha (Erα), insulin-like growth factor 1 receptor beta (IGF-1Rβ), prion protein (PrP), voltage-dependent anion channel 1 (VDAC1)), scaffolding proteins (caeolin-1 and flotilin-1), trace biometals (Cu, Se, Zn, Mn) and related molecules (transferrin), antioxidant/detoxifying enzyme activities (superoxide dismutase (SOD), glutathione peroxidase 4, glutathione-S-transferase, butyrylcholinesterase), and also in oxidative stress-related metabolites (malondialdehyde) reflected in the CSF of individuals diagnosed SMC or MCI [ 29, 92 ]. The essential concept of these observations is that these changes reflect biochemical changes occurring in the brain parenchyma in aged individual during initial stages of cognitive alterations, irrespective of whether subjects will develop any type of dementia.…”

“…Indeed, as observed in Fig. 2B and 2C , highly significant relationships between factors scores obtained by multivariate factor analyses and the In-Out-test punctuations in two different biochemical approaches [ 29, 92 ]. In the first one ( Fig.…”

“…In the first one ( Fig. 2B ), based on the ER-signalosome multiprotein complex [ 29 ], factor scores from principal component 1 were highly determined by ERα and IGF-1Rβ as CSF protein markers and IGF-1Rβ/Flotilin-1 and PrP/flotillin-1 as protein ratios. PC1 displayed a significant negative relationship with In-Out scores, with group subjects consistently distributed along the regression line ( Fig.…”

Roles of traditional chinese medicine regulating neuroendocrinology on AD treatment

“…Recent studies have shown that imbalances in various neuroendocrine related systems, such as the HPA axis, HPG axis, insulin and brain-gut axis, can be observed in people with early stage AD, while related hormone therapy has been proved to achieve better results only in the early stages of aging ( 84 , 85 ). This suggests that the intervention of AD through the neuroendocrine related axis needs to be carried out before the irreversible accumulation of neurotoxic substances, and there is still a large gap in the relevant early drug treatment in western medicine intervention.…”