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Phosphorylation plays a key role in Alzheimer's disease (AD) pathogenesis, impacting distinct processes such as amyloid-beta (Aβ) peptide production and tau phosphorylation. Impaired phosphorylation events contribute to senile plaques and neurofibrillary tangles' formation, two major histopathological hallmarks of AD. Blood-derived extracellular particles (bdEP) can represent a disease-related source of phosphobiomarker candidates, and hence, in this pilot study, bdEP of Control and AD cases were analyzed by a targeted phosphoproteomics approach using a high-density microarray that featured at least 1145 pan-specific and 913 phosphosite-specific antibodies. This approach, innovatively applied to bdEP, allowed the identification of 150 proteins whose expression levels and/or phosphorylation patterns were significantly altered across AD cases. Gene Ontology enrichment and Reactome pathway analysis unraveled potentially relevant molecular targets and disease-associated pathways, and protein-protein interaction networks were constructed to highlight key targets. The discriminatory value of both the total proteome and the phosphoproteome was evaluated by univariate and multivariate approaches. This pilot experiment supports that bdEP are enriched in phosphotargets relevant in an AD context, holding value as peripheral biomarker candidates for disease diagnosis.

Background: Alzheimer's disease (AD) diagnosis is difficult, and new accurate tools based on peripheral biofluids are urgently needed. Extracellular vesicles (EVs) emerged as a valuable source of biomarker profiles for AD, since their cargo is disease-specific and these can be easily isolated from easily accessible biofluids, as blood. Fourier Transform Infrared (FTIR) spectroscopy can be employed to analyze EVs and obtain the spectroscopic profiles from different regions of the spectra, simultaneously characterizing carbohydrates, nucleic acids, proteins, and lipids., Objective: The aim of this study was to identify blood-derived EVs (bdEVs) spectroscopic signatures with AD discriminatory potential., Methods: Herein, FTIR spectra of bdEVs from two biofluids (serum and plasma) and distinct sets of Controls and AD cases were acquired, and EVs' spectra analyzed., Results: Analysis of bdEVs second derivative peaks area revealed differences between Controls and AD cases in distinct spectra regions, assigned to carbohydrates and nucleic acids, amides, and lipids., Conclusions: EVs' spectroscopic profiles presented AD discriminatory value, supporting the use of bdEVs combined with FTIR as a screening or complementary tool for AD diagnosis.

With the increase in life expectancy, the incidence of neurodegenerative disorders and their impact worldwide has been increasing in recent years. Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, have complex and varied mechanisms of pathogenesis. Importantly, they share the common feature of disrupted circadian rhythms. This hallmark is believed to underlie the symptoms of such diseases and even potentially contribute to their onset. In addition, the association of physical frailty with dementia and neurodegenerative disorders has been demonstrated. In fact, frail persons are 8 times more likely to have some form of dementia and population studies report a significant prevalence for frailty in older patients with AD and PD. SIRT1 regulates the acetylation status of clock components and controls circadian amplitude of clock genes. However, the mechanisms responsible for this circadian clock control have been the subject of contradictory findings. Importantly, the activation of SIRT1 has been shown to have very relevant therapeutic potential against neurodegeneration. Nevertheless, few studies have attempted to connect the therapeutic reestablishing of SIRT1 as an approach against circadian disruption in neurodegenerative diseases. In this review, we address: circadian rhythms as an important early biomarker of neurodegenerative disorders; mechanisms for SIRT1 activation and the novel sirtuin-activating compounds (STACs); SIRT1 circadian paradox and subsequent studies in an unprecedented way in the literature; the beneficial role of SIRT1 activation in neurodegeneration; innovative proposals of how circadian-based interventions (e.g., SIRT1 activators) may become an important therapeutic approach against neurodegenerative disorders and how non-pharmacologic interventions (e.g., Mediterranean-style diet) might help in the prevention and/or treatment of these high-burden disorders, while tackling frailty and enhancing robustness., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

MicroRNAs (miRNAs) have emerged as a class of small, endogenous, regulatory RNAs that exhibit the ability to epigenetically modulate the translation of mRNAs into proteins. This feature enables them to control cell phenotypes and, consequently, modify cell function in a disease context. The role of inflammatory miRNAs in Alzheimer's disease (AD) and their ability to modulate glia responses are now beginning to be explored. In this study, we propose to disclose the functional role of miR-155, one of the most well studied immune-related miRNAs in AD-associated neuroinflammatory events, employing the 3xTg AD animal model. A strong upregulation of miR-155 levels was observed in the brain of 12-month-old 3xTg AD animals. This event occurred simultaneously with an increase of microglia and astrocyte activation, and before the appearance of extracellular Aβ aggregates, suggesting that less complex Aβ species, such as Aβ oligomers may contribute to early neuroinflammation. In addition, we investigated the contribution of miR-155 and the c-Jun transcription factor to the molecular mechanisms that underlie Aβ-mediated activation of glial cells. Our results suggest early miR-155 and c-Jun upregulation in the 3xTg AD mice, as well as in Aβ-activated microglia and astrocytes, thus contributing to the production of inflammatory mediators such as IL-6 and IFN-β. This effect is associated with a miR-155-dependent decrease of suppressor of cytokine signaling 1. Furthermore, since c-Jun silencing decreases the levels of miR-155 in Aβ-activated microglia and astrocytes, we propose that miR-155 targeting can constitute an interesting and promising approach to control neuroinflammation in AD., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Alzheimer's and Parkinson's diseases represent the most prevalent neurodegenerative disorders worldwide. Current pharmacological or surgical treatments provide symptomatic benefits, particularly in the early stages, but none can delay or stop the progression of these diseases. There is an urgent need for new therapies able to modify disease progression. Gene therapy, mainly based on viral vectors, is presently being assumed as an important alternative to conventional treatments. After decades of preclinical developments, we are now facing an important period, in which several viral vector-mediated gene therapies are being tested in Phase 1 and Phase 2 clinical trials, with some of them showing promising results. This review intends to present an overview of the current efforts in the field for the treatment of Alzheimer's and Parkinson's diseases.