Developmental mechanisms of Alzheimer’s disease

Alzheimerova bolest je kronična neurodegenerativna bolest s dobro definiranim patofiziološkim mehanizmima koji najčešće utječu na područja medijalnog temporalnog režnja i susjedne neokortikalne strukture. Ekstracelularni neuralni plakovi i inercelularni fibrili su najpoznatije patološke značajke Alzheimerove bolesti, a nastaju zbog akumulacije amiloid β peptida i citoskeletnih promjena koje proizlaze iz hiperfosforilacije i agregacije mikrotubul vezujućeg tau proteina. Nakon originalno uspostavljene amiloidne teroije prema kojoj je amiloid β bio glavni nositelj patologije AD istraživanjima je utvrđeno da tau protein svojom agregacijom u oligomere i fibrile uvelike doprinosi progresiji same bolesti. Unatoč brojnim istraživanjima patologije AD i dalje ostaje nepoznato zašto razvoj bolesti traje desetljećima prije pojave prvih simptoma, no smatra se da bi tome mogao biti razlog smanjena sposobnost uklanjanja pogrešno smotanih, oligomernih i agregiranih oblika tau proteina koji se nakupljaju starenjem. Nakon neuspješnih terapijskih intervencija usmjerenih na amiloid β noviji lijekovi za cilj imaju fosforilaciju i agregaciju tau proteina, te se još čekaju ishodi njihovih kliničkih studija. Također od velike važnosti za projektiranje novih terapeutika je i točno razumijevanje mehanizama kojima se toksični tau oligomeri šire kroz sinapsu.Alzheimer's disease is a chronic neurodegenerative disease with well-defined pathophysiological mechanisms that most often affect the medial temporal lobe and adjacent neocortical structures. Extracellular neural plaques and intercellular fibrils are most common pathological features of Alzheimer's disease, resulting from the accumulation of amyloid β peptides and cytoskeletal changes resulting from hyperphosphorylation and aggregation of microtubule binding tau protein. After the originally established amyloid theory according to which amyloid β was the main bearer of AD pathology, was found that tau protein by its aggregation into oligomers and fibrils greatly contributes to the progression of the disease as well. Despite the numerous studies of AD pathology, it remains unknown why the development of the disease lasts decades before the appearance of the first symptoms, but it is considered that the reason could be diminished ability to remove misfolded, oligomeric and aggregated forms of protein, which accumulate with age. Following unsuccessful therapeutic interventions that target amyloid β, new drugs are aiming at phosphorylation and aggregation of tau protein but we are still awaiting the outcomes of their clinical studies. In addition, the accurate understanding of the mechanisms by which the toxic tau oligomers are spread through the synapse is of great importance for the design of new therapies

Developmental mechanisms of Alzheimer’s disease

Alzheimerova bolest je kronična neurodegenerativna bolest s dobro definiranim patofiziološkim mehanizmima koji najčešće utječu na područja medijalnog temporalnog režnja i susjedne neokortikalne strukture. Ekstracelularni neuralni plakovi i inercelularni fibrili su najpoznatije patološke značajke Alzheimerove bolesti, a nastaju zbog akumulacije amiloid β peptida i citoskeletnih promjena koje proizlaze iz hiperfosforilacije i agregacije mikrotubul vezujućeg tau proteina. Nakon originalno uspostavljene amiloidne teroije prema kojoj je amiloid β bio glavni nositelj patologije AD istraživanjima je utvrđeno da tau protein svojom agregacijom u oligomere i fibrile uvelike doprinosi progresiji same bolesti. Unatoč brojnim istraživanjima patologije AD i dalje ostaje nepoznato zašto razvoj bolesti traje desetljećima prije pojave prvih simptoma, no smatra se da bi tome mogao biti razlog smanjena sposobnost uklanjanja pogrešno smotanih, oligomernih i agregiranih oblika tau proteina koji se nakupljaju starenjem. Nakon neuspješnih terapijskih intervencija usmjerenih na amiloid β noviji lijekovi za cilj imaju fosforilaciju i agregaciju tau proteina, te se još čekaju ishodi njihovih kliničkih studija. Također od velike važnosti za projektiranje novih terapeutika je i točno razumijevanje mehanizama kojima se toksični tau oligomeri šire kroz sinapsu.Alzheimer's disease is a chronic neurodegenerative disease with well-defined pathophysiological mechanisms that most often affect the medial temporal lobe and adjacent neocortical structures. Extracellular neural plaques and intercellular fibrils are most common pathological features of Alzheimer's disease, resulting from the accumulation of amyloid β peptides and cytoskeletal changes resulting from hyperphosphorylation and aggregation of microtubule binding tau protein. After the originally established amyloid theory according to which amyloid β was the main bearer of AD pathology, was found that tau protein by its aggregation into oligomers and fibrils greatly contributes to the progression of the disease as well. Despite the numerous studies of AD pathology, it remains unknown why the development of the disease lasts decades before the appearance of the first symptoms, but it is considered that the reason could be diminished ability to remove misfolded, oligomeric and aggregated forms of protein, which accumulate with age. Following unsuccessful therapeutic interventions that target amyloid β, new drugs are aiming at phosphorylation and aggregation of tau protein but we are still awaiting the outcomes of their clinical studies. In addition, the accurate understanding of the mechanisms by which the toxic tau oligomers are spread through the synapse is of great importance for the design of new therapies

Developmental mechanisms of Alzheimer’s disease

Alzheimerova bolest je kronična neurodegenerativna bolest s dobro definiranim patofiziološkim mehanizmima koji najčešće utječu na područja medijalnog temporalnog režnja i susjedne neokortikalne strukture. Ekstracelularni neuralni plakovi i inercelularni fibrili su najpoznatije patološke značajke Alzheimerove bolesti, a nastaju zbog akumulacije amiloid β peptida i citoskeletnih promjena koje proizlaze iz hiperfosforilacije i agregacije mikrotubul vezujućeg tau proteina. Nakon originalno uspostavljene amiloidne teroije prema kojoj je amiloid β bio glavni nositelj patologije AD istraživanjima je utvrđeno da tau protein svojom agregacijom u oligomere i fibrile uvelike doprinosi progresiji same bolesti. Unatoč brojnim istraživanjima patologije AD i dalje ostaje nepoznato zašto razvoj bolesti traje desetljećima prije pojave prvih simptoma, no smatra se da bi tome mogao biti razlog smanjena sposobnost uklanjanja pogrešno smotanih, oligomernih i agregiranih oblika tau proteina koji se nakupljaju starenjem. Nakon neuspješnih terapijskih intervencija usmjerenih na amiloid β noviji lijekovi za cilj imaju fosforilaciju i agregaciju tau proteina, te se još čekaju ishodi njihovih kliničkih studija. Također od velike važnosti za projektiranje novih terapeutika je i točno razumijevanje mehanizama kojima se toksični tau oligomeri šire kroz sinapsu.Alzheimer's disease is a chronic neurodegenerative disease with well-defined pathophysiological mechanisms that most often affect the medial temporal lobe and adjacent neocortical structures. Extracellular neural plaques and intercellular fibrils are most common pathological features of Alzheimer's disease, resulting from the accumulation of amyloid β peptides and cytoskeletal changes resulting from hyperphosphorylation and aggregation of microtubule binding tau protein. After the originally established amyloid theory according to which amyloid β was the main bearer of AD pathology, was found that tau protein by its aggregation into oligomers and fibrils greatly contributes to the progression of the disease as well. Despite the numerous studies of AD pathology, it remains unknown why the development of the disease lasts decades before the appearance of the first symptoms, but it is considered that the reason could be diminished ability to remove misfolded, oligomeric and aggregated forms of protein, which accumulate with age. Following unsuccessful therapeutic interventions that target amyloid β, new drugs are aiming at phosphorylation and aggregation of tau protein but we are still awaiting the outcomes of their clinical studies. In addition, the accurate understanding of the mechanisms by which the toxic tau oligomers are spread through the synapse is of great importance for the design of new therapies

Infectious Agents as Potential Drivers of α-Synucleinopathies.

International audienceα-synucleinopathies, encompassing Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, are devastating neurodegenerative diseases for which available therapeutic options are scarce, mostly because of our limited understanding of their pathophysiology. Although these pathologies are attributed to an intracellular accumulation of the α-synuclein protein in the nervous system with subsequent neuronal loss, the trigger(s) of this accumulation is/are not clearly identified. Among the existing hypotheses, interest in the hypothesis advocating the involvement of infectious agents in the onset of these diseases is renewed. In this article, we aimed to review the ongoing relevant factors favoring and opposing this hypothesis, focusing on (1) the potential antimicrobial role of α-synuclein, (2) potential entry points of pathogens in regard to early symptoms of diverse α-synucleinopathies, (3) pre-existing literature reviews assessing potential associations between infectious agents and Parkinson's disease, (4) original studies assessing these associations for dementia with Lewy bodies and multiple system atrophy (identified through a systematic literature review), and finally (5) potential susceptibility factors modulating the effects of infectious agents on the nervous system. © 2022 International Parkinson and Movement Disorder Society

Caffeine intake exerts dual genome-wide effects on hippocampal metabolism and learning-dependent transcription

Caffeine is the most consumed psychoactive substance worldwide. Strikingly, molecular pathways engaged by its regular consumption remain unclear. We herein addressed the mechanisms associated with habitual (chronic) caffeine consumption in the mouse hippocampus using untargeted orthogonal-omics techniques. Our results revealed that chronic caffeine exerts concerted pleiotropic effects in the hippocampus, at the epigenomic, proteomic and metabolomic levels. Caffeine lowers metabolic-related processes in the bulk tissue, while it induces neuronal-specific epigenetic changes at synaptic transmission/plasticity-related genes and increased experience-driven transcriptional activity. Altogether, these findings suggest that regular caffeine intake improves the signal-to-noise ratio during information encoding, in part through a fine-tuning of metabolic genes while boosting the salience of information processing during learning in neuronal circuits.This work was supported by grants from Hauts-de-France (PARTEN-AIRR, COGNADORA; START-AIRR, INS-SPECT) and Programs d’Investissements d’Avenir LabEx (excellence laboratory) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease) and EGID (European Genomic Institute for Diabetes ANR-10LABX-46). Our laboratories are also supported by ANR (GRAND to LB, ADORATAU, ADORASTrAU, METABOTAU to DB and BETAPLASTICITY to JSA), COEN (5008), Fondation pour la Recherche Médicale, France Alzheimer/Fondation de France, FHU VasCog research network (Lille, France), Fondation Vaincre Alzheimer (ADOMEMOTAU), European Foundation for the Study of Diabetes (EFSD to JSA), Fondation Plan Alzheimer as well as Inserm, CNRS, Université Lille, Lille Métropole Communauté Urbaine, DN2M. KC hold a doctoral grant from Lille University. VG-M was supported by Fondation pour la Recherche Médicale (SPF20160936000). CM was supported by Région Hauts753 30 754 de-France. ALB is supported by CNRS, Unistra (Strasbourg, France), ANR-16-CE92-0031 755 756 757 758 759 760 761 762 (EPIFUS), ANR-18-CE16-0008-02 (ADORASTrAU), Alsace Alzheimer 67, France Alzheimer (AAP SM 2017 #1664). IP is supported by Fondation pour la Recherche Médicale (SPF201909009162). CEM is grateful for the support by the Alzheimer Forschung Initiative e.V. (AFI, Düsseldorf, Germany). LC was funded by SIF Italian Society of Pharmacology. RAC was supported by LaCaixa Foundation (LCF/PR/HP17/52190001) and FCT (POCI-01-0145-FEDER-03127). Santa Casa da Misericórdia (MB-7-2018) and CEECIND/01497/2017 to LVL