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Amyloid β (Aβ) peptides accumulating in the brain are proposed to trigger Alzheimer's disease (AD). However, molecular cascades underlying their toxicity are poorly defined. Here, we explored a novel hypothesis for Aβ42 toxicity that arises from its proven affinity for γ-secretases. We hypothesized that the reported increases in Aβ42, particularly in the endolysosomal compartment, promote the establishment of a product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events. We conducted kinetic analyses of γ-secretase activity in cell-free systems in the presence of Aβ, as well as cell-based and ex vivo assays in neuronal cell lines, neurons, and brain synaptosomes to assess the impact of Aβ on γ-secretases. We show that human Aβ42 peptides, but neither murine Aβ42 nor human Aβ17-42 (p3), inhibit γ-secretases and trigger accumulation of unprocessed substrates in neurons, including C-terminal fragments (CTFs) of APP, p75, and pan-cadherin. Moreover, Aβ42 treatment dysregulated cellular homeostasis, as shown by the induction of p75-dependent neuronal death in two distinct cellular systems. Our findings raise the possibility that pathological elevations in Aβ42 contribute to cellular toxicity via the γ-secretase inhibition, and provide a novel conceptual framework to address Aβ toxicity in the context of γ-secretase-dependent homeostatic signaling., Competing Interests: KZ, UD, SL, TE, MM, MH, MF, BÖ, DG, DK, AB, CH, MV, OB, LC No competing interests declared, WM consulted for Samumed and AC immune. He served on advisory boards for the Bluefield Project to Cure Frontotemporal Dementia, the Blythedale-Burke Pediatric Neuroscience Research Collaboration, The Key, the National Down Syndrome Society, the American Neurological Association, the Sanford Health Lorraine Cross Award Committee, the NIH COBRE program at the University of Nebraska, the Dementia Aware Committee and the Dementia Committee for the State of California Health Services, and the San Diego Alzheimer's Project. He was a member of a Pfizer Data Safety Monitoring Board. WM is a co-inventor on UCSD Patents for Gamma-secretase Modulators. WM received grant or contract funding from the NIH, Ono Pharma Foundation, Cure Alzheimer Fund, DH Chen Foundation, AC Immune, Larry L Hillblom Foundation, Alzheimer Association, Annovis-Bio and BioSplice and the Michael J Fox Foundation. He received a travel reimbursement from AC Immune. Annovis Bio provided a gift to the WM lab and a test compound, (© 2023, Zoltowska et al.)

The discovery of surrogate biomarkers reflecting neuronal dysfunction in neurodegenerative diseases (NDDs) remains an active area of research. To boost these efforts, we demonstrate the utility of publicly available datasets for probing the pathogenic relevance of candidate markers in NDDs. As a starting point, we introduce the readers to several open access resources, which contain gene expression profiles and proteomics datasets from patient studies in common NDDs, including proteomics analyses of cerebrospinal fluid (CSF). Then, we illustrate the method for curated gene expression analyses across select brain regions from four cohorts of Parkinson disease patients (and from one study in common NDDs), probing glutathione biogenesis, calcium signaling and autophagy. These data are complemented by findings of select markers in CSF-based studies in NDDs. Additionally, we enclose several annotated microarray studies, and summarize reports on CSF proteomics across the NDDs, which the readers can utilize for translational purposes. We anticipate that this "beginner's guide" will benefit the research community in NDDs, and would serve as a useful educational tool., (© 2023. The Author(s).)

Defects in brain energy metabolism and proteopathic stress are implicated in age-related degenerative neuronopathies, exemplified by Alzheimer's disease (AD) and Parkinson's disease (PD). As the currently available drug regimens largely aim to mitigate cognitive decline and/or motor symptoms, there is a dire need for mechanism-based therapies that can be used to improve neuronal function and potentially slow down the underlying disease processes. In this context, a new class of pharmacological agents that achieve improved glycaemic control via the glucagon-like peptide 1 (GLP-1) receptor has attracted significant attention as putative neuroprotective agents. The experimental evidence supporting their potential therapeutic value, mainly derived from cellular and animal models of AD and PD, has been discussed in several research reports and review opinions recently. In this review article, we discuss the pathological relevance of derangements in the neurovascular unit and the significance of neuron-glia metabolic coupling in AD and PD. With this context, we also discuss some unresolved questions with regard to the potential benefits of GLP-1 agonists on the neurovascular unit (NVU), and provide examples of novel experimental paradigms that could be useful in improving our understanding regarding the neuroprotective mode of action associated with these agents.

Abstract: Gomes Moreira, D, José Brito, C, de Almeida Ferreira, JJ, Bouzas Marins, JC, López Díaz de Durana, A, Couceiro Canalejo, J, Butragueño Revenga, J, and Sillero-Quintana, M. Lactate concentration is related to skin temperature variation after a specific incremental judo test. J Strength Cond Res 35(8): 2213-2221, 2021-This study aimed to analyze the skin temperature (tsk) response in judokas after a specific incremental test and to determine whether anthropometric and physiological measures can be explained by the variation in mean tsk. A total of 23 male judo athletes (age: 20.1 ± 4.7 years; height: 173.1 ± 8.1 cm; and body mass: 71.7 ± 8.1 kg) performed a specific incremental judo test. Skin temperature evaluations were collected in 26 regions of interest (ROIs), and the mean tsk was calculated using an equation including 10 of them. The time points before the test (pre-test), immediately after (0 minutes), and after 5, 10, and 15 minutes of the test were established to measure the tsk, mean tsk, auricular temperature (tau), and blood lactate (LAC). The athletes completed a mean of 7.0 ± 1.0 stages of the test, 95% confidence interval (CI; 6.2-7.1). The V̇o2peak achieved was 48.7 ± 5.3 ml·kg-1·min-1, 95% CI (46.4-51.0). Compared with pre-test values, only the forehead significantly decreased 5 minutes after the test (p < 0.05). The posterior right arm and posterior left arm remained increased 10 minutes after the test (p < 0.05). After 15 minutes, 19 of the 26 ROIs analyzed were significantly decreased (p < 0.05). Among all tested models of linear regression, only 2 were significant, the difference of tsk 5 minutes compared with pre-test (F1, 21 = 16.49, p = 0.001) and the difference of tsk 10 minutes compared with pre-test, to predict LAC concentration at the end of the test (F1, 21 = 9.30, p = 0.006). We concluded that 5 minutes after the test, the judokas present a higher tau and a higher tsk in 7 ROIs, and the tsk decreases 15 minutes after the test in 19 of the considered ROIs. The variation of mean tsk 5 and 10 minutes after the test compared with pre-test values is associated with blood LAC at the end of the test., (Copyright © 2019 National Strength and Conditioning Association.)