Functional and effective EEG connectivity patterns in Alzheimer’s disease and mild cognitive impairment: a systematic review

BackgroundAlzheimer’s disease (AD) might be best conceptualized as a disconnection syndrome, such that symptoms may be largely attributable to disrupted communication between brain regions, rather than to deterioration within discrete systems. EEG is uniquely capable of directly and non-invasively measuring neural activity with precise temporal resolution; connectivity quantifies the relationships between such signals in different brain regions. EEG research on connectivity in AD and mild cognitive impairment (MCI), often considered a prodromal phase of AD, has produced mixed results and has yet to be synthesized for comprehensive review. Thus, we performed a systematic review of EEG connectivity in MCI and AD participants compared with cognitively healthy older adult controls.MethodsWe searched PsycINFO, PubMed, and Web of Science for peer-reviewed studies in English on EEG, connectivity, and MCI/AD relative to controls. Of 1,344 initial matches, 124 articles were ultimately included in the systematic review.ResultsThe included studies primarily analyzed coherence, phase-locked, and graph theory metrics. The influence of factors such as demographics, design, and approach was integrated and discussed. An overarching pattern emerged of lower connectivity in both MCI and AD compared to healthy controls, which was most prominent in the alpha band, and most consistent in AD. In the minority of studies reporting greater connectivity, theta band was most commonly implicated in both AD and MCI, followed by alpha. The overall prevalence of alpha effects may indicate its potential to provide insight into nuanced changes associated with AD-related networks, with the caveat that most studies were during the resting state where alpha is the dominant frequency. When greater connectivity was reported in MCI, it was primarily during task engagement, suggesting compensatory resources may be employed. In AD, greater connectivity was most common during rest, suggesting compensatory resources during task engagement may already be exhausted.ConclusionThe review highlighted EEG connectivity as a powerful tool to advance understanding of AD-related changes in brain communication. We address the need for including demographic and methodological details, using source space connectivity, and extending this work to cognitively healthy older adults with AD risk toward advancing early AD detection and intervention

Prion Protein Is a Key Determinant of Alcohol Sensitivity through the Modulation of N-Methyl-D-Aspartate Receptor (NMDAR) Activity

The prion protein (PrP) is absolutely required for the development of prion diseases; nevertheless, its physiological functions in the central nervous system remain elusive. Using a combination of behavioral, electrophysiological and biochemical approaches in transgenic mouse models, we provide strong evidence for a crucial role of PrP in alcohol sensitivity. Indeed, PrP knock out (PrP−/−) mice presented a greater sensitivity to the sedative effects of EtOH compared to wild-type (wt) control mice. Conversely, compared to wt mice, those over-expressing mouse, human or hamster PrP genes presented a relative insensitivity to ethanol-induced sedation. An acute tolerance (i.e. reversion) to ethanol inhibition of N-methyl-D-aspartate (NMDA) receptor-mediated excitatory post-synaptic potentials in hippocampal slices developed slower in PrP−/− mice than in wt mice. We show that PrP is required to induce acute tolerance to ethanol by activating a Src-protein tyrosine kinase-dependent intracellular signaling pathway. In an attempt to decipher the molecular mechanisms underlying PrP-dependent ethanol effect, we looked for changes in lipid raft features in hippocampus of ethanol-treated wt mice compared to PrP−/− mice. Ethanol induced rapid and transient changes of buoyancy of lipid raft-associated proteins in hippocampus of wt but not PrP−/− mice suggesting a possible mechanistic link for PrP-dependent signal transduction. Together, our results reveal a hitherto unknown physiological role of PrP on the regulation of NMDAR activity and highlight its crucial role in synaptic functions

Involvment of Cytosolic and Mitochondrial GSK-3β in Mitochondrial Dysfunction and Neuronal Cell Death of MPTP/MPP+-Treated Neurons

Aberrant mitochondrial function appears to play a central role in dopaminergic neuronal loss in Parkinson's disease (PD). 1-methyl-4-phenylpyridinium iodide (MPP+), the active metabolite of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is a selective inhibitor of mitochondrial complex I and is widely used in rodent and cell models to elicit neurochemical alterations associated with PD. Recent findings suggest that Glycogen Synthase Kinase-3β (GSK-3β), a critical activator of neuronal apoptosis, is involved in the dopaminergic cell death. In this study, the role of GSK-3β in modulating MPP+-induced mitochondrial dysfunction and neuronal death was examined in vivo, and in two neuronal cell models namely primary cultured and immortalized neurons. In both cell models, MPTP/MPP+ treatment caused cell death associated with time- and concentration-dependent activation of GSK-3β, evidenced by the increased level of the active form of the kinase, i.e. GSK-3β phosphorylated at tyrosine 216 residue. Using immunocytochemistry and subcellular fractionation techniques, we showed that GSK-3β partially localized within mitochondria in both neuronal cell models. Moreover, MPP+ treatment induced a significant decrease of the specific phospho-Tyr216-GSK-3β labeling in mitochondria concomitantly with an increase into the cytosol. Using two distinct fluorescent probes, we showed that MPP+ induced cell death through the depolarization of mitochondrial membrane potential. Inhibition of GSK-3β activity using well-characterized inhibitors, LiCl and kenpaullone, and RNA interference, prevented MPP+-induced cell death by blocking mitochondrial membrane potential changes and subsequent caspase-9 and -3 activation. These results indicate that GSK-3β is a critical mediator of MPTP/MPP+-induced neurotoxicity through its ability to regulate mitochondrial functions. Inhibition of GSK-3β activity might provide protection against mitochondrial stress-induced cell death

Expression of Heterologous PrP and Prion Propagation in RK13 Cells

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Lethal recessive myelin toxicity of prion protein lacking its central domain

PrP(C)-deficient mice expressing prion protein variants with large amino-proximal deletions (termed PrP(ΔF)) suffer from neurodegeneration, which is rescued by full-length PrP(C). We now report that expression of PrP(ΔCD), a PrP variant lacking 40 central residues (94–134), induces a rapidly progressive, lethal phenotype with extensive central and peripheral myelin degeneration. This phenotype was rescued dose-dependently by coexpression of full-length PrP(C) or PrP(C) lacking all octarepeats. Expression of a PrP(C) variant lacking eight residues (114–121) was innocuous in the presence or absence of full-length PrP(C), yet enhanced the toxicity of PrP(ΔCD) and diminished that of PrP(ΔF). Therefore, deletion of the entire central domain generates a strong recessive-negative mutant of PrP(C), whereas removal of residues 114–121 creates a partial agonist with context-dependent action. These findings suggest that myelin integrity is maintained by a constitutively active neurotrophic protein complex involving PrP(C), whose effector domain encompasses residues 94–134

Cellular prion protein mediates early apoptotic proteome alternation and phospho-modification in human neuroblastoma cells

Anti-apoptotic properties of physiological and elevated levels of the cellular prion protein (PrP(c)) under stress conditions are well documented. Yet, detrimental effects of elevated PrP(c) levels under stress conditions, such as exposure to staurosporine (STS) have also been described. In the present study, we focused on discerning early apoptotic STS-induced proteome and phospho-proteome changes in SH-SY5Y human neuroblastoma cells stably transfected either with an empty or PRNP-containing vector, expressing physiological or supraphysiological levels of PrP(c), respectively. PrP(c)-overexpression per se appears to stress the cells under STS-free conditions as indicated by diminished cell viability of PrP(c)-overexpressing versus control cells. However, PrP(c)-overexpression becomes advantageous following exposure to STS. Thus, only a short exposure (2 h) to 1 μM STS results in lower survival rates and significantly higher caspase-3 activity in control versus PrP(c)-overexpressing cells. Hence, by exposing both experimental groups to the same apoptotic conditions we were able to induce apoptosis in control, but not in PrP(c)-overexpressing cells (as assessed by caspase-3 activity), which allowed for filtering out proteins possibly contributing to protection against STS-induced apoptosis in PrP(c)-overexpressing cells. Among other proteins regulated by different PrP(c) levels following exposure to STS, those involved in maintenance of cytoskeleton integrity caught our attention. In particular, the finding that elevated PrP(c) levels significantly reduce profilin-1 (PFN-1) expression. PFN-1 is known to facilitate STS-induced apoptosis. Silencing of PFN-1 expression by siRNA significantly increased viability of PrP(c)-overexpressing versus control cells, under STS treatment. In addition, PrP(c)-overexpressing cells depleted of PFN-1 exhibited increased viability versus PrP(c)-overexpressing cells with preserved PFN-1 expression, both subjected to STS. Concomitant increase in caspase-3 activity was observed in control versus PrP(c)-overexpressing cells after treatment with siRNA- PFN-1 and STS. We suggest that reduction of PFN-1 expression by elevated levels of PrP(c) may contribute to protective effects PrP(c)-overexpressing SH-SY5Y cells confer against STS-induced apoptosis