Geoffrey Canet

Metabotropic glutamate receptor 5 (mGlu5) is essential for synaptic plasticity and memory, making it a potential therapeutic target in Alzheimer’s disease (AD). While hemispheric asymmetries in hippocampal function have been observed in AD patients, the lateralized contribution of mGlu5 signaling to cognitive decline remains unclear. Here, we show a physiological left-right asymmetry in hippocampal mGlu5 expression in wild-type mice, with higher levels in the left hemisphere, consistent with previous reports. This physiological asymmetry is lost in two distinct mouse models of AD, the J20 and 5xFAD mice, revealing a hemisphere-specific disruption of hippocampal mGlu5 regulation. Using the light-controllable negative allosteric modulator Alloswitch-1, we show that selective inhibition of left, but not right, hippocampal mGlu5 restores working and short-term memory in AD mice. This finding indicates that altered mGlu5 expression does not simply reflect receptor loss, but rather a dysregulated signaling state that remains functionally relevant and pharmacologically targetable. Left-specific modulation also normalizes pathological downstream signaling, including aberrant Pyk2 and GSK-3β activation and tau hyperphosphorylation, across both hemispheres, indicating a widespread impact of hemisphere-selective intervention. These findings establish a functional lateralization of hippocampal mGlu5 signaling and identify the left hippocampus as a critical site for mGlu5-dependent memory dysfunction in AD. They also highlight the therapeutic potential of region-specific photopharmacology for precise intervention in early AD pathology, providing a strategy for spatially targeted modulation of pathological synaptic signaling in neurodegenerative disease.

La maladie d’Alzheimer (MA) se caractérise au niveau cérébral par l’agrégation des peptides β-amyloïdes (Aβ) à partir du clivage de la protéine précurseur de l’amyloïde (APP), et par l’hyperphosphorylation de la protéine Tau. Dans la MA, les déficits cognitifs sont associés une dérégulation précoce de l’axe endocrinien du stress (axe hypothalamo-hypophyso-surrénalien ou HPA), à la surproduction conséquente de glucocorticoïdes (GC) et au dysfonctionnement de leurs récepteurs (GR). De nombreuses études montrent l’implication des GR dans la MA, notamment en favorisant la production d’Aβ et l’hyperphosphorylation de Tau. Dans un modèle aigu de la MA (injection icv d’une solution oligomérique de peptides oAβ25-35 chez le rat), nous avons observé un dysfonctionnement de l’axe HPA, associé à un ensemble d’altérations cellulaires rappelant la physiopathologie humaine. Il existe un cercle vicieux dans lequel la pathologie induit une surproduction de GC qui en retour potentialise la MA. L’objectif de ma thèse était donc de casser ce cercle vicieux à l’aide d’une nouvelle classe de molécules agissant comme des modulateurs sélectifs des GR (sGRm), afin de ralentir ou de renverser le décours de la pathologie. Les sGRm ont la particularité d'abroger les effets pathologiques des GR, tout en conservant leur signalisation physiologique. Dans une première étude, nous avons montré dans le modèle oAβ25-35 qu’un sGRm, le CORT113176, renversait dans l'hippocampe la totalité des modifications induites par la toxicité amyloïde (déficits de mémoire à court terme, taux de GC plasmatiques élevés, déficits synaptiques, neuroinflammation, apoptose et augmentation de la synthèse d'Aβ). Dans une deuxième étude, nous avons réalisé des analyses dans le cortex préfrontal. Cette structure d’intérêt dans la MA est également très riche en GR, suggérant que cette région est très sensible à la dérégulation de l’axe HPA. Ici, nous avons utilisé le sGRm comme outil pour caractériser l’implication des GR dans un certain nombre de voies de signalisations intracellulaires. Nous avons notamment observé l’état de phosphorylation des GR, leurs chaperonnes (HSP90/70), l’équilibre entre les voies de clivage amyloïdogénique et non-amyloïdogénique ou encore des enzymes impliquées dans la phosphorylation de GR et de Tau (GSK-3β, Cdk5, Calpain-1, Fyn). Les GR semblent être impliqués dans un grand nombre de processus associés à la toxicité induite par l’oAβ25-35, et le CORT113176 permet de renverser cette toxicité, mettant en avant le rôle central des GR dans la physiopathologie de la MA. Dans une dernière étude, suite à l'ensemble de ces premiers résultats, et afin de valider l'intérêt thérapeutique du CORT113176, nous avons tenté d’amener la preuve de concept via deux approches complémentaires. Tout d’abord, nous avons testé la robustesse du traitement avec le sGRm dans le modèle oAβ25-35 afin d’observer si le fait de casser le cercle vicieux en restaurant la physiologie de l’axe HPA, des GC et des GR permettait de lutter à long terme contre la pathologie. Les premiers résultats montrent que le CORT113176 renverse à long terme la toxicité amyloïde sur les paramètres mesurés précédemment, mais semble également renverser l’hyperphosphorylation de Tau. Enfin, nous avons voulu confirmer l’intérêt thérapeutique de casser le cercle vicieux dans un modèle de souris transgénique, la souris J20 (transgène de l’APP humain muté). Chez des animaux de 9 mois, le CORT113176 semble à nouveau renverser un grand nombre de marqueurs associés à la MA. L’ensemble de ces résultats place l’axe HPA et les GR au cœur de la physiopathologie de la MA, pouvant faire le lien entre la toxicité amyloïde et l’hyperphosphorylation de Tau. Ces travaux mettent également en évidence l’approche prometteuse représentée par les sGRm qui casse le cercle vicieux entre la dérégulation de l’axe HPA et la toxicité amyloïde, en rétablissant le rôle primaire des GC et des GR dans le maintien de l’homéostasie.

A recent case study reported a PSEN2 mutation carrier with high amyloid burden but unexpectedly restricted tau pathology and preserved cognition. While genetic and proteomic factors were explored, the patient's lifelong occupational heat exposure may represent an overlooked contributor to resilience. We highlight evidence from preclinical, clinical, and epidemiological studies suggesting that elevated body temperature promotes tau clearance via enhanced proteostasis. This observation invites deeper investigation into thermoregulation as a modifiable factor in tau homeostasis and Alzheimer's disease vulnerability, with implications for both biomarker interpretation and therapeutic strategies targeting tau-mediated neurodegeneration.

Background: Aggregates of hyperphosphorylated tau protein are a hallmark of Alzheimer's disease (AD) and other tauopathies. Sleep disturbances—common in AD—have been associated with altered tau phosphorylation and secretion in both animal models and humans, and insufficient sleep is recognized as a potential risk factor for AD. Moreover, sleep deprivation affects mRNA splicing, polyadenylation, and miRNA‐mediated degradation. However, how tau phosphorylation, secretion, and splicing are physiologically regulated across the sleep–wake cycle remains unknown. Method: Here, we combine in vitro, in vivo and clinical methods to investigate whether tau phosphorylation, secretion and splicing are governed by circadian rhythms linked to sleep and body temperature (BT). To elucidate underlying mechanisms, we exposed neuronal cells to the physiological temperatures observed under each condition. Result: We found that tau phosphorylation undergoes sleep‐driven circadian variations, as it is hyperphosphorylated during sleep, when BT is lower. Similar changes in tau phosphorylation were reproduced in neuronal cells exposed to temperatures recorded during the sleep–wake cycle. In addition, we reveal a novel pathway by which BT modulates tau secretion, with higher temperature increasing extracellular and circulating tau levels. Tau splicing also varied with temperature, as lower temperatures favored exon 10 exclusion. Finally, in humans, the increase in CSF tau levels observed post‐wakefulness correlated with BT increase during wakefulness. Conclusion: Overall, these findings demonstrate that tau phosphorylation, secretion, and splicing follow a circadian pattern primarily regulated by BT and sleep. Given the prevalence of sleep disruptions and thermoregulatory deficits in AD, this study offers new insight into how tau pathology may develop and spread.

RyR1-related myopathies (RyR1-RMs) include a wide range of genetic disorders that result from mutations in the RYR1 gene. Pathogenic variants lead to defective intracellular calcium homeostasis and muscle dysfunction. Fixing intracellular calcium leaks by stabilizing the RyR1 calcium channel has been identified as a promising therapeutic target. Gene therapy via prime editing also holds great promise as it can cure diseases by correcting genetic mutations. However, as more than 700 variants have been identified in the RYR1 gene, a universal treatment would be a more suitable solution for patients. Our investigation into the RyR1-S2843A mutation has yielded promising results. Using a calcium leak assay, we determined that the S2843A mutation was protective when combined with pathogenic mutations and significantly reduced the Ca²⁺ leak of the RyR1 channel. Our study demonstrated that prime editing can efficiently introduce the protective S2843A mutation. In vitro experiments using the RNA electroporation of the prime editing components in human myoblasts achieved a 31% introduction of this mutation. This article lays the foundation for a new therapeutic approach for RyR1-RM, where a unique once-in-a-lifetime prime editing treatment could potentially be universally applied to all patients with a leaky RyR1 channel.

Sleep disturbance is bidirectionally associated with an increased risk of Alzheimer’s disease and other tauopathies. While the sleep-wake cycle regulates interstitial and cerebrospinal fluid (CSF) tau levels, the underlying mechanisms remain unknown. Understanding these mechanisms is crucial, given the evidence that tau pathology spreads through neuron-to-neuron transfer, involving the secretion and internalization of pathological tau forms. Here, we combined in vitro, in vivo, and clinical methods to reveal a pathway by which changes in body temperature (BT) over the sleep-wake cycle modulate extracellular tau levels. In mice, a higher BT during wakefulness and sleep deprivation increased CSF and plasma tau levels, while also upregulating unconventional protein secretion pathway I (UPS-I) events including (a) intracellular tau dephosphorylation, (b) caspase 3–mediated cleavage of tau (TauC3), and (c) membrane translocation of tau through binding to phosphatidylinositol 4,5-bisphosphate (PIP ₂ ) and syndecan 3. In humans, the increase in CSF and plasma tau levels observed after wakefulness correlated with BT increases during wakefulness. By demonstrating that sleep-wake variation in BT regulates extracellular tau levels, our findings highlight the importance of thermoregulation in linking sleep disturbances to tau-mediated neurodegeneration and the preventative potential of thermal interventions.

Background and Purpose: Exposure to chronic stress and high levels of glucocorticoid hormones in adulthood has been associated with cognitive deficits and increased risk of Alzheimer's disease (AD). Dazucorilant has recently emerged as a selective glucocorticoid receptor (NR3C1) modulator, exhibiting efficacy in counteracting amyloid‐β toxicity in an acute model of AD. We aim to assess the therapeutic potential of dazucorilant in reversing amyloid and tau pathologies through the inhibition of glucocorticoid receptor pathological activity, and providing additional evidence for its consideration in AD treatment.Experimental Approach: The efficacy of dazucorilant was evaluated in two transgenic mouse models of amyloid pathology. The slowly progressing J20 and the aggressively pathological 5xFAD mice. Behavioural analysis was conducted to evaluate welfare, cognitive performances and anxiety levels. The activity of the glucocorticoid receptor system, neuroinflammation, amyloid burden and tau phosphorylation were examined in hippocampi.Key Results: In both AD models, chronic treatment with dazucorilant improved working and long‐term spatial memories along with the inhibition of glucocorticoid receptor‐dependent pathogenic processes and the normalization of plasma glucocorticoid levels. Dazucorilant treatment also resulted in a reduction in tau hyperphosphorylation and amyloid production and aggregation. Additionally, dazucorilant seemed to mediate a specific re‐localization of activated glial cells onto amyloid plaques in J20 mice, suggesting a restoration of physiological neuroinflammatory processes.Conclusion and Implications: Dazucorilant exhibited sustained disease‐modifying effects in two AD models. Given that this compound has demonstrated safety and tolerability in human subjects, our results provide pre‐clinical support for conducting clinical trials to evaluate its potential in AD.

This scientific commentary refers to ‘Proteostasis as a fundamental principle of Tau immunotherapy’ by Cruz et al. (https://doi.org/10.1093/brain/awae254).

The sleep-wake cycle regulates interstitial fluid and cerebrospinal fluid (CSF) tau levels in both mouse and human by mechanisms that remain unestablished. Here, we reveal a novel pathway by which wakefulness increases extracellular tau levels in mouse and humans. In mice, higher body temperature (BT) associated with wakefulness and sleep deprivation increased CSF tau. In vitro, wakefulness temperatures upregulated tau secretion via a temperature-dependent increase in activity and expression of unconventional protein secretion pathway-1 components, namely caspase-3-mediated C-terminal cleavage of tau (TauC3), and membrane expression of PIP₂ and syndecan-3. In humans, the increase in both CSF and plasma tau levels observed post-wakefulness correlated with BT increase during wakefulness. Our findings suggest sleep-wake variation in BT may contribute to regulating extracellular tau levels, highlighting the importance of thermoregulation in pathways linking sleep disturbance to neurodegeneration, and the potential for thermal intervention to prevent or delay tau-mediated neurodegeneration.