Explore the vast range of titles available.

The family of VPS10p-Domain (D) receptors comprises five members named SorLA, Sortilin, SorCS1, SorCS2 and SorCS3. While their physiological roles remain incompletely resolved, they have been recognized for their signaling engagements and trafficking abilities, navigating a number of molecules between endosome, Golgi compartments, and the cell surface. Strikingly, recent studies connected all the VPS10p-D receptors to Alzheimer’s disease (AD) development. In addition, they have been also associated with diseases comorbid with AD such as diabetes mellitus and major depressive disorder. This systematic review elaborates on genetic, functional, and mechanistic insights into how dysfunction in VPS10p-D receptors may contribute to AD etiology, AD onset diversity, and AD comorbidities. Starting with their functions in controlling cellular trafficking of amyloid precursor protein and the metabolism of the amyloid beta peptide, we present and exemplify how these receptors, despite being structurally similar, regulate various and distinct cellular events involved in AD. This includes a plethora of signaling crosstalks that impact on neuronal survival, neuronal wiring, neuronal polarity, and synaptic plasticity. Signaling activities of the VPS10p-D receptors are especially linked, but not limited to, the regulation of neuronal fitness and apoptosis via their physical interaction with pro- and mature neurotrophins and their receptors. By compiling the functional versatility of VPS10p-D receptors and their interactions with AD-related pathways, we aim to further propel the AD research towards VPS10p-D receptor family, knowledge that may lead to new diagnostic markers and therapeutic strategies for AD patients.

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.

Sorting protein–related receptor containing LDLR class A repeats (SORLA; also known as LR11) exerts intraneuronal trafficking functions in the central nervous system. Recently, involvement of SORLA in retinogenesis was proposed, but no studies have examined yet in detail the expression pattern of this sorting receptor in the retina. Here, we provide a spatio-temporal characterization of SORL1 mRNA and its translational product SORLA in the postnatal mouse retina. Using stereological analysis, we confirmed previous studies showing that receptor depletion in knockout mice significantly reduces the number of cells in the inner nuclear layer (INL), suggesting that functional SORLA expression is essential for the development of this retinal strata. qPCR and Western blot analyses showed that SORL1/SORLA expression peaks at postnatal day 15, just after eye opening. Interestingly, we found that transcripts are somatically located in several neuronal populations residing in the INL and the ganglion cell layer, whereas SORLA protein is also present in the synaptic plexiform layers. In line with receptor expression in dendritic terminals, we found delayed stratification of the inner plexiform layer in knockout mice, indicating an involvement of SORLA in neuronal connectivity. Altogether, these data suggest a novel role of SORLA in synaptogenesis. Receptor dysfunctions may be implicated in morphological and functional impairments of retinal inner layer formation associated with eye disorders.

SORL1 is strongly associated with both sporadic and familial forms of Alzheimer’s disease (AD), but a lack of information about alternatively spliced transcripts currently limits our understanding of the role of SORL1 in AD. Here, we describe a SORL1 transcript ( SORL1-38b ) characterized by inclusion of a novel exon (E38b) that encodes a truncated protein. We identified E38b-containing transcripts in several brain regions, with the highest expression in the cerebellum and showed that SORL1-38b is largely located in neuronal dendrites, which is in contrast to the somatic distribution of transcripts encoding the full-length SORLA protein ( SORL1-fl ). SORL1-38b transcript levels were significantly reduced in AD cerebellum in three independent cohorts of postmortem brains, whereas no changes were observed for SORL1-fl . A trend of lower 38b transcript level in cerebellum was found for individuals carrying the risk variant at rs2282649 (known as SNP24), although not reaching statistical significance. These findings suggest synaptic functions for SORL1-38b in the brain, uncovering novel aspects of SORL1 that can be further explored in AD research.

We report the case of a woman who presented cryptogenic temporal lobe seizures from the age of 43 years. Antiepileptic drug (AED) treatment with carbamazepine was able to control seizures for 1 year, but seizures relapsed and an add-on treatment with lamotrigine was started without achieving seizures control. The patient's  medical history was unremarkable except for a mild hirsutism for which she was taking finasteride since 45 years of age. In view of the possible relationship between finasteride, a known inhibitor of neurosteroids synthesis, and patient's seizures exacerbation, we stopped finasteride resulting in prompt recovery of seizures control. It is know that 5α-dihydrosteroids are precursors of powerful positive modulators of γ-aminobutyric acid-A  inhibitory currents and exert antiseizure effects in animal epilepsy models. This case supports the hypothesis that endogenous neurosteroids can modulate seizure susceptibility and response to AEDs also in humans, suggesting their possible use as a new therapeutic option.

Emerging studies have identified changes in lipid processing in Alzheimer's disease patients. However, how the various brain cell types respond to these changes is unclear. Multiple Alzheimer's disease risk genes are expressed in microglia and involved in lipid sensing and processing. In this project, we assessed unbiasedly how various fatty acids impact microglia states and functions. Using the iPSC-derived microglia platform, our lab has recently developed (Dolan*, Therrien* et al. Nature Immunology 2023), we characterized the impact of 48 different fatty acids on human microglia. We identified 5 distinct transcriptional signatures produced in response to various lipids, including a toxic lipotoxicity signature independent of TREM2 signaling. Using microglia villages, we assessed the toxicity across 25 iPSC donors and identified genetic modifiers of microglia lipotoxicity. Together, our data identifies genetic regulators of microglia states and presents new insight into understanding how to protect synapses in Alzheimer's that could lead to new therapies and biomarkers for early diagnoses.

Background Emerging studies have identified changes in lipid processing in Alzheimer’s disease patients. However, how the various brain cell types respond to these changes is unclear. Multiple Alzheimer’s disease risk genes are expressed in microglia and involved in lipid sensing and processing. Method In this project, we assessed unbiasedly how various fatty acids impact microglia states and functions. Using the iPSC‐derived microglia platform, our lab has recently developed (Dolan*, Therrien* et al. Nature Immunology 2023), we characterized the impact of 48 different fatty acids on human microglia. Result We identified 5 distinct transcriptional signatures produced in response to various lipids, including a toxic lipotoxicity signature independent of TREM2 signaling. Using microglia villages, we assessed the toxicity across 25 iPSC donors and identified genetic modifiers of microglia lipotoxicity. Conclusion Together, our data identifies genetic regulators of microglia states and presents new insight into understanding how to protect synapses in Alzheimer’s that could lead to new therapies and biomarkers for early diagnoses.

Background SORL1 encodes the retromer‐associated receptor SORLA that functions in endosomal recycling. Rare variants in SORL1 have been associated with Alzheimer’s disease (AD) and rare pathogenic variants are estimated to occur in up to 2.75% of early onset AD patients and in 1.5% of unrelated late onset AD patients. While truncation mutations are observed almost exclusively in AD patients, it is currently unknown which among the hundreds of rare missense variants identified in SORL1, are pathogenic. Method Here we address this question by relying on SORLA’s distinct molecular architecture. First, we completed a structure‐guided sequence alignment for all the protein domains. Next, we identified proteins that contain domains homologous to those of SORLA, which include pathogenic variants for monogenic diseases. Result We identified the analogous domain positions of these variants in the SORLA protein sequence and showed that variants in these positions similarly impair SORL1, and lead to AD. Together, our findings represent a comprehensive study on SORLA protein variation and functional effects, which allowed us to prioritize SORL1 genetic variants into high or moderate priority mutations. Conclusion We envision that our findings will be used by clinical geneticists for assessing variants they identify in patients, allowing further development of diagnostic procedures and patient counseling strategies. Ultimately, the identification of the most pathogenic variants will inform investigations into the molecular mechanisms of endosomal recycling which will support the development of therapeutic treatment strategies for SORL1 variant‐carrying patients.

Purpose Non allergic rhinitis (NAR) comprises different clinical definitions and phenotypes, including non inflammatory non allergic (NINAR) and cellular inflammatory forms. Nasal cytology, usually performed by scraping the inferior turbinate, is a non invasive, cheap and point-of-care tool to distinguish among the different NAR phenotypes, but still a relevant proportion of patients evaluated by nasal cytology receive a non precise definition of NAR phenotype. We hypothesize that collecting nasal cytology samples from middle meatus could increase the diagnostic accuracy. Methods Consecutive patients with chronic rhinitis without evidence of allergic sensitization were assessed for nasal cytology by means of scraping both the inferior turbinate and the middle meatus (lateral-inferior wall of the middle turbinate). Results 107 consecutive patients with NAR were enrolled in the study. According to inferior turbinate cytology, 42.1% were defined as affected by NINAR, 2.8% by bacterial rhinitis, 10.3% by non allergic rhinitis with eosinophils (NARES), 15.0% non allergic rhinitis with neutrophils (NARNE), 19.6% non allergic rhinitis with mast-cells (NARMA) and 10.3% non allergic rhinitis with eosinophils and mast-cells (NARESMA). Middle meatus cytology was in accordance with inferior turbinate cytology in only 37.6% of cases. Eosinophils and mast-cells were detectable more frequently in middle meatus samples (49.5% vs 19.6%, p  < 0.01, 59.8% vs 29.9%, p  < 0.01, respectively). 93.3% of NINAR patients received an inflammatory NAR phenotype at middle meatus cytology: 26.7% NARES, 24.4% NARNE, 31.1% NARMA and 11.1% NARESMA. Conclusion Middle meatus cytology is more reliable than inferior turbinate cytology in phenotyping patients with NAR. Our study strengthen that nasal cytology should be implemented in clinical practice collecting samples at the middle meatus level.

SORL1 encodes the retromer-associated receptor SORLA that functions in endosomal recycling. Rare variants in SORL1 have been associated with Alzheimer's disease (AD) and rare pathogenic variants are estimated to occur in up to 2.75% of early onset AD patients and in 1.5% of unrelated late onset AD patients. While truncation mutations are observed almost exclusively in AD patients, it is currently unknown which among the hundreds of rare missense variants identified in SORL1, are pathogenic. Here we address this question by relying on SORLA's distinct molecular architecture. First, we completed a structure-guided sequence alignment for all the protein domains. Next, we identified proteins that contain domains homologous to those of SORLA, which include pathogenic variants for monogenic diseases. We identified the analogous domain positions of these variants in the SORLA protein sequence and showed that variants in these positions similarly impair SORL1, and lead to AD. Together, our findings represent a comprehensive study on SORLA protein variation and functional effects, which allowed us to prioritize SORL1 genetic variants into high or moderate priority mutations. We envision that our findings will be used by clinical geneticists for assessing variants they identify in patients, allowing further development of diagnostic procedures and patient counseling strategies. Ultimately, the identification of the most pathogenic variants will inform investigations into the molecular mechanisms of endosomal recycling which will support the development of therapeutic treatment strategies for SORL1 variant-carrying patients.