Certains cas de maladie d'Alzheimer sont-ils déclenchés par une forme de diabète dans le cerveau ?

- Posted in Certains cas de maladie d'Alzheimer sont-ils déclenchés par une forme de diabète dans le cerveau ? by Français by

On sait depuis 2017 que certaines personnes atteintes de diabète de type 2 ont un risque plus élevé de développer la maladie d'Alzheimer.

Une variante de l'un des principaux gènes impliqués dans la maladie d'Alzheimer: APOE4, semble interférer avec la capacité des cellules cérébrales à utiliser l'insuline, ce qui peut éventuellement provoquer le stress (en quelque sorte l'état de famine) et la mort des cellules nerveuses. Officieusement, on appelle parfois cela: Le diabète de type 3.

L'insuline régule le métabolisme des glucides, des lipides et des protéines en favorisant l'absorption du glucose du sang par le foie, les graisses et les cellules musculaires squelettiques.

Des concentrations élevées d'insuline dans le sang inhibent fortement la production et la sécrétion de glucose par le foie. L'insuline circulante affecte également la synthèse des protéines (augmentation de la masse tissulaire) dans une grande variété de tissus.

A l'inverse, de faibles niveaux d'insuline dans le sang ont l'effet inverse en favorisant un catabolisme (fonte des tissus) généralisé, en particulier de la graisse corporelle de réserve.

On pense que chez personnes diabétiques, l'utilisation ou la signalisation de l'insuline par leur cerveau ne fonctionne pas. Leur risque de développer la maladie d'Alzheimer est environ 10 à 15 fois plus élevé.

Ce nouvel article de Gemma Salvadó et ses collègues apporte davantage d'informations sur ce sujet.

L'activation gliale (les cellules nerveuses autres que les neurones) est l'un des premiers mécanismes à être altérés dans la maladie d'Alzheimer. enter image description here

La protéine acide fibrillaire gliale (GFAP) est une protéine protéine de filament intermédiaire (IF) qui est exprimée par de nombreux types de cellules du système nerveux central (SNC), y compris les astrocytes.

Il existe de multiples troubles associés à une mauvaise régulation de la GFAP, et une blessure peut provoquer une réaction néfaste des cellules gliales. La cicatrisation gliale est une conséquence de plusieurs conditions neurodégénératives, ainsi que des blessures qui sectionnent le matériel neural. La cicatrice est formée par des astrocytes interagissant avec le tissu fibreux pour rétablir les marges gliales autour du noyau central de la lésion et est partiellement causée par une régulation à la hausse de la GFAP.

La protéine acide fibrillaire gliale est liée à l'astrogliose réactive (la destruction des astrocytes, des cellules nerveuses différentes des neurones) et peut être mesurée à la fois dans le liquide céphalo-rachidien et le sang.

Il a été suggéré que la GFAP plasmatique soit modifiée plus tôt dans la maladie d'Alzheimer que son homologue du liquide céphalo-rachidien.

Bien que les astrocytes consomment environ la moitié de l'énergie dérivée du glucose dans le cerveau, la relation entre l'astrogliose réactive et le métabolisme cérébral du glucose est mal comprise. Le fluorodésoxyglucose (FDG) est un analogue du glucose marqué avec un isotope émetteur de positrons (18F) qui permet de mesurer la consommation cérébrale régionale de glucose à l'aide de la tomographie par émission de positons (TEP).

Les auteurs espagnols visaient à étudier l'association entre l'absorption de fluorodésoxyglucose (FDG) et l'astrogliose réactive, au moyen de GFAP quantifié à la fois dans le plasma et le liquide céphalo-rachidien pour les mêmes participants. GFAP est une protéine de filament intermédiaire astrocytaire, principalement exprimée dans le cerveau.

La cohorte ALFA a caractérisé la maladie d'Alzheimer préclinique chez 2743 individus sans troubles cognitifs, âgés de 45 à 75 ans, et enrichie pour les antécédents familiaux de maladie d'Alzheimer sporadique. Dans cette cohorte de parents, 419 participants ALFA +  ont été sélectionnés pour être préférentiellement porteurs d'APOE-ε4 et/ou pour être des enfants adultes de patients AD. Ces participants ont subi une évaluation plus complète incluant une ponction lombaire et une TEP Aβ et [18F]FDG.

Pour cette étude, les auteurs ont inclus 314 participants sans troubles cognitifs de la cohorte ALFA+, dont 112 étaient positifs à l'amyloïde-β. Les associations entre les marqueurs GFAP et l'absorption de [18F]FDG ont été étudiées. Les auteurs ont également cherché à savoir si ces associations étaient modifiées par le statut Aβ et tau.

La GFAP plasmatique était positivement associée à la consommation de glucose dans tout le cerveau, tandis que les associations de GFAP du liquide céphalo-rachidien avec l'absorption de [18F]FDG n'ont été observées que dans des zones spécifiques plus petites comme le pôle temporal et le lobe temporal supérieur.

Ces associations ont persisté lors de la prise en compte des biomarqueurs de la pathologie Aβ, mais sont devenues négatives chez les participants Aβ-positifs et tau-positifs dans des domaines similaires de l'hypométabolisme lié à la maladie d'Alzheimer.

Une réactivité astrocytaire plus élevée, probablement en réponse aux changements pathologiques précoces de la maladie d'Alzheimer, est liée à une consommation de glucose plus élevée. Avec l'apparition de la pathologie tau, le découplage observé entre les biomarqueurs astrocytaires et la consommation de glucose pourrait indiquer une incapacité à maintenir les demandes énergétiques plus élevées requises par les astrocytes réactifs.

Lisez l'article original sur Pubmed

Functional cooperation of α-synuclein and tau is essential for proper corticogenesis.

- Posted in Functional cooperation of α-synuclein and tau is essential for proper corticogenesis. by English by

Corticogenesis is the process in which the cerebral cortex of the brain is formed during the development of the nervous system. The cortex is the outer layer of the brain and is composed of up to six layers. Neurons formed in the ventricular zone migrate to their final locations in one of the six layers of the cortex. The process occurs between gestational weeks seven to 18 in humans.

Alpha-synuclein and tau are abundant multifunctional neuronal proteins, and their intracellular deposits have been linked to many neurodegenerative diseases. The Alzheimer's disease is defined by extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles composed of hyperphosphorylated tau protein.

However, accumulating evidence suggests that the presynaptic protein α-synuclein, which is usually associated with synucleinopathies like Parkinson's disease, is also involved in the pathophysiology of AD.

Despite the disease relevance, Alpha-synuclein and tau physiological roles remain elusive, as mice with knockout of either of these genes do not exhibit overt phenotypes.

Shengming Wang and colleagues from China and Japan, hypothesized functional cooperation of αSyn and tau during corticogenesis. To reveal this cooperation, they generated a mice model where αSyn and tau genes were deleted and characterized the functional crosstalk between these proteins during brain development.

Intriguingly, deletion of αSyn and tau reduced Notch signaling and accelerated interkinetic nuclear migration of G2 phase at early embryonic stage.

This significantly altered the balance between the proliferative and neurogenic divisions of progenitor cells, resulting in an overproduction of early-born neurons and enhanced neurogenesis, by which the brain size was enlarged during the embryonic stage in both sexes.

On the other hand, loss of αSyn and tau also perturbed gliogenesis at later embryonic stage, as well as the subsequent glial expansion and maturation at postnatal brain. The expansion and maturation of macroglial cells were suppressed in the αSyntau postnatal brain, which in turn reduced the male αSyntau brain size and cortical thickness to less than the control values.

The authors' findings provide new mechanistic insights and extend therapeutic opportunities for neurodegenerative diseases caused by aberrant αSyn and tau.

Read the original article on Pubmed

Neuroimaging analyses from a randomized, controlled study to evaluate plasma exchange with albumin replacement in mild-to-moderate Alzheimer's disease: additional results from the AMBAR study.

- Posted in Neuroimaging analyses from a randomized, controlled study to evaluate plasma exchange with albumin replacement in mild-to-moderate Alzheimer's disease: additional results from the AMBAR study. by English by

Plasma exchange (PE) with albumin replacement is currently being investigated by several organisations as a new therapeutic approach for Alzheimer's disease (AD). enter image description here

Routine PE removal of an AD patient's plasma would favor elimination of albumin‐bound β amyloid , and possibly, other pathogenic elements. In addition, replacement with fresh therapeutic albumin can restore the antioxidant capacity of AD patient plasma, as albumin is highly oxidized and glycated. Furthermore, a therapeutic action at the vascular level can have a positive impact on dementia.

This new study by Gemma Cuberas-Borrós and colleagues from Spain, was designed to detect structural and functional brain changes in Alzheimer's disease patients treated with therapeutic plasma exchange with albumin replacement, as part of the recent AMBAR phase 2b/3 clinical trial. The AMBAR trial enrolled patients at 41 sites: 19 in Spain and 22 in the USA.

Mild-to-moderate Alzheimer's disease patients were randomized into four arms: three arms receiving plasma exchange with albumin, and a placebo arm.

There were two phases for treatment administration:

  • During intensive treatment phase, the three treatment groups received weekly conventional therapeutic PE (TPE) with albumin (Albutein® 5%, Grifols) replacement, through peripheral or central venous access, for 6 weeks.
  • This was followed by a 12-month maintenance period with monthly low-volume PE (LVPE) during which three different treatment modalities were administered.

During the 12-month maintenance period: - one group received LVPE with low-dose (20 g; 100 mL) 20% albumin (Albutein® 20%, Grifols); - one group received low-dose albumin alternated with low-dose (10 g; 200 mL) IVIG (Flebogamma® 5% DIF, Grifols) every 4 months; - one group received high-dose (40 g; 200 mL) 20% albumin alternated with high-dose (20 g; 400 mL) IVIG every 4 months.

The high albumin + IVIG group showed no statistically significant reduction of right hippocampus. MRI analyses of selected subcortical structures showed fewer volume changes from baseline to final visit in the high albumin + IVIG treatment group. I.e., the smallest percent decline in metabolism, and least progression of defect compared to placebo.

Particularly in moderate AD patients, there was a significant difference in the extension of defect pattern between high albumin + IVIG and the rest of treatment arms.

Read the original article on Pubmed

Intelligent lesion blood-brain barrier targeting nano-missiles for Alzheimer's disease treatment by anti-neuroinflammation and neuroprotection.

- Posted in Intelligent lesion blood-brain barrier targeting nano-missiles for Alzheimer's disease treatment by anti-neuroinflammation and neuroprotection. by English by

Neuroinflammation, is characterized by excessively activated glial cells and overexpressed inflammatory factors in Alzheimer’s disease (AD).

Nonsteroidal anti-inflammatory drugs (NSAIDs) are most widely used drugs in inhibiting NF-κB signaling pathway, and high-dose of ibuprofen have been confirmed to improve dementia-like symptoms in AD animal models.

Therefore, anti-neuroinflammatory treatment might undermine the positive feedback loop of neuroinflammation and neuronal dysfunction.

But ibuprofen can't make neuronal damages reversed to cure AD completely. So it is necessary to use additional neuroprotective drugs . Calcineurin inhibitor (tacrolimus, FK506), is one of the most effective neuroprotective drug in central nervous system diseases. Moreover, the amelioration of AD-like behavior has been observed in patients taking FK506 enter image description here Xueqin He, Huile Gao from Sichuan and Macau universities, established an ibuprofen and FK506 encapsulated drug co-delivery system, which can target the receptor of advanced glycation endproducts and response to the high level of reactive oxygen species in Alzheimer's disease.

Methods used to get through the blood–brain barrier (BBB) may entail the use of endogenous transport systems, including carrier-mediated transporters (CMT), such as glucose and amino acid carriers, receptor-mediated transcytosis for insulin or transferrin, and the blocking of active efflux transporters such as p-glycoprotein.

Yet traditional CMT-based brain targeting delivery leads to unselective distribution in whole brain because of the homogenous expression of targeted receptors on BBB31. It is therefore important to find targets that are restrictively expressed on BBB of lesion. In AD lesion sites, the receptor of advanced glycation endproducts (RAGE) is specifically and highly expressed on the diseased neurovascular unit, including cerebral vascular endothelial cells, astrocytes and neurons.

As RAGE is highly and specifically expressed on the lesion neurovascular unit of Alzheimer's disease, this property helps to improve specificity of drug targeting the system and reduce unselective distribution in normal brain.

RAP peptide (sequence: CELKVLMEKEL) is a specific ligand of RAGE, which could assist with the transportation of nanoparticles into diseased brain parenchyma through CMT.

Thus, ibuprofen and FK506 delivery can be specifically released in astrocytes of Alzheimer's disease lesion in response to high levels of ROS.

As a result, the cognition of Alzheimer's disease mice was significantly improved and the quantity of A plaques was decreased. Neurotoxicity was also alleviated with structural regeneration and functional recovery of neurons. Besides, the neuroinflammation dominated by NF-B pathway was significantly inhibited with decreased NF-B and IL-1 in the brain. enter image description here Overall, Ibu&[email protected] can efficiently and successively target diseased BBB and astrocytes in Alzheimer's disease lesion. Thus it significantly treats Alzheimer's disease by anti-neuroinflammation and neuroprotection.

Read the original article on Pubmed

Are some cases of Alzheimer's disease triggered by a form of diabetes in the brain?

- Posted in Are some cases of Alzheimer's disease triggered by a form of diabetes in the brain? by English by

It's known since 2017 that some people with Type 2 diabetes have a higher risk of Alzheimer's disease.

A variant of the so-called Alzheimer’s gene, APOE4, seems to interfere with brain cells' ability to use insulin, which may eventually cause the cells to starve and die. Unofficially, it's called Type 3 diabetes. What it refers to is that their brain's insulin utilization or signaling is not functioning. Their risk of developing Alzheimer’s disease is about 10 to 15 times higher.

This new article by Gemma Salvadó and colleagues adds more information on this topic. Glial activation is one of the earliest mechanisms to be altered in Alzheimer's disease. Glial fibrillary acidic protein relates to reactive astrogliosis and can be measured in both cerebrospinal fluid and blood.

Plasma GFAP has been suggested to become altered earlier in Alzheimer's disease than its cerebrospinal fluid counterpart.

Although astrocytes consume approximately half of the glucose-derived energy in the brain, the relationship between reactive astrogliosis and cerebral glucose metabolism is poorly understood. Fluorodeoxyglucose (FDG) is a glucose analog labeled with a positron emitter isotope (18F) that allows measurement of regional cerebral glucose consumption using positron emission tomography (PET).

The Spanish authors aimed to investigate the association between fluorodeoxyglucose (FDG) uptake and reactive astrogliosis, by means of GFAP quantified in both plasma and cerebrospinal fluid for the same participants. GFAP is an astrocytic intermediate filament protein, mainly expressed in the brain.

The ALFA cohort characterized preclinical AD in 2743 cognitively unimpaired individuals, aged between 45 and 75 years old, and enriched for family history of sporadic AD. From this parent cohort, 419 ALFA + participants were selected to be preferentially APOE-ε4 carriers and/or to be adult children of AD patients. These participants underwent a more comprehensive evaluation including a lumbar puncture and an Aβ and [18F]FDG PET.

For this study, the authors included 314 cognitively unimpaired participants from the ALFA + cohort, 112 of whom were amyloid-β positive. Associations between GFAP markers and [18F]FDG uptake were studied.
The authors also investigated whether these associations were modified by Aβ and tau status.

Plasma GFAP was positively associated with glucose consumption in the whole brain, while cerebrospinal fluid GFAP associations with [18F]FDG uptake were only observed in specific smaller areas like temporal pole and superior temporal lobe. These associations persisted when accounting for biomarkers of Aβ pathology but became negative in Aβ-positive and tau-positive participants in similar areas of Alzheimer's disease-related hypometabolism.

Higher astrocytic reactivity, probably in response to early Alzheimer's disease pathological changes, is related to higher glucose consumption. With the onset of tau pathology, the observed uncoupling between astrocytic biomarkers and glucose consumption might be indicative of a failure to sustain the higher energetic demands required by reactive astrocytes.

Read the original article on Pubmed

Insights for Alzheimer's disease pharmacotherapy and current clinical trials.

- Posted in Insights for Alzheimer's disease pharmacotherapy and current clinical trials. by English by

Over the years, the scientific community has sought improvements in the life quality of patients diagnosed with Alzheimer's disease. Synaptic loss and neuronal death observed in the regions responsible for cognitive functions represent an irreversible progressive disease that is clinically characterized by impaired cognitive and functional abilities, along with behavioral symptoms. Currently, image and body fluid biomarkers can provide early dementia diagnostic, being it the best way to slow the disease's progression. The first signs of Alzheimer's disease development are still complex, the existence of individual genetic and phenotypic characteristics about the disease makes it difficult to standardize studies on the subject. The answer seems to be related between Aβ and tau proteins. Aβ deposition in the medial parietal cortex appears to be the initial stage of Alzheimer's disease, but it does not have a strong correlation with neurodegeneration. The strongest link between symptoms occurs with tau aggregation, which antecede Aβ deposits in the medial temporal lobe, however, the protein can be found in cognitively healthy older people. The answer to the question may lie in some catalytic effect between both proteins. Amid so many doubts, Aducanumab was approved, which raised controversies and results intense debate in the scientific field. Abnormal singling of some blood biomarkers produced by adipocytes under high lipogenesis, such as TNFα, leptin, and interleukin-6, demonstrate to be linked to neuroinflammation worsens, diabetes, and also severe cases of COVID-19, howsoever, under higher lipolysis, seem to have therapeutic anti-inflammatory effects in the brain, which has increasingly contributed to the understanding of Alzheimer's disease. In addition, the relationship of severe clinical complications caused by Sars-CoV-2 viral infection and Alzheimer's disease, go beyond the term "risk group" and may be related to the development of dementia long-term.

Thus, this review summarized the current emerging pharmacotherapies, alternative treatments, and nanotechnology applied in clinical trials, discussing relevant points that may contribute to a more accurate look.

Read the original article on Pubmed

Blood exchange and Alzheimer's disease

- Posted in Blood exchange and Alzheimer's disease by English by

It's known since some time that there is a link between blood and Alzheimer disease.

For example in 2019, after being dosed with GRF6021, a drug proposed by Alkahest, a California-based startup, Alzheimer's patients in a clinical trial retained memory and mental function for six months - when they would normally be expected to deteriorate. GRF6021, a drug proposed by Alkahest, a California-based startup, is made from the blood of young people.

On contrary a large study found that people who experienced a blood transfusion may be at risk of Alzheimer's disease or may be, because they were transfused with "old blood".

A research team led by Claudio Soto, in the Department of Neurology with McGovern Medical School at UTHealth Houston, with Akihiko Urayama, as first author, performed a series of whole blood exchange treatments to partially replace blood from mice exhibiting Alzheimer's disease-causing amyloid precursor proteins with complete blood from healthy mice of the same genetic background.

The results of the study was published in Molecular Psychiatry.

The development of cerebral amyloid plaques in a transgenic mice model of AD (Tg2576) was significantly reduced by 40–80% through exchanging whole blood with normal blood from wild type mice having the same genetic background. Importantly, such reduction resulted in improvement in spatial memory performance in aged Tg2576 mice.

The exact mechanism by which blood exchange reduces amyloid pathology and improves memory is presently unknown, but measurements of Aβ in plasma soon after blood exchange suggest that mobilization of Aβ from the brain to blood may be implicated.

Their results suggest that a target for AD therapy may exist in the peripheral circulation, which could open a novel disease-modifying intervention for AD. Technologies commonly used in medical practice, such as plasmapheresis or blood dialysis, could 'clean' blood from Alzheimer's patients, reducing the buildup of toxic substances in the brain.

This was suggested recently.

EU Awards €2.5M for Potential Vaccine for ALS Tied to C9orf72 Gene

- Posted in EU Awards €2.5M for Potential Vaccine for ALS Tied to C9orf72 Gene by English by

Intravacc, a contract development and manufacturing organization (CDMO) of preventive and therapeutic vaccines and the German Center for Neurogenerative Diseases (DZNE), have been awarded a funding of € 2.5 million from the European Union (EIC Transition Grant) to further develop a prototype C9orf72 ALS vaccine.

Mutations in C9orf72 gene causes excessive repeats of six nucleotides GGGGCC. These extra repeats lead to the production of abnormal proteins, called dipeptide repeat proteins (DPR). Moreover, excessive GGGGCC repeats in the C9orf72 gene also are one of the most common causes of frontotemporal dementia (FTD).

Researchers from the German Center for Neurogenerative Diseases hypothesized that using a vaccine to induce the production of such antibodies by the body’s immune system could be a potential therapy for ALS and FTD linked to C9orf72 gene mutations.

This is a concept close to ASO, but it would make the body continuously targeting those repeats, while ASO work only for a short time after administration.

In recent years, there has been increasing interest in the use of monoclonal antibodies to treat neurodegenerative disorders, with the goal of targeting misfolded intra- or extra-cellular proteins, such as amyloid beta peptide, tau, or alpha-synuclein.

Very recently, the U.S. FDA has approved Aducanumab, a recombinant monoclonal antibody against amyloid beta plaques, for the treatment of Alzheimer's disease patients.

Antibodies show a considerable number of advantages when used for therapeutic purposes. They possess a long half-life, and, due to their nature, they can efficiently target proteins in their physiological state, after post-translational modifications or in a misfolded conformation, with high specificity and affinity.

Yet there were many pre-clinical studies involving antibodies against SOD1 or TDP-43 without much success. In 2019 a study had more success with C9orf72.

Antibodies are big molecules and might pose difficulties in penetrating the CNS due to the natural defense structure of the blood-brain barrier (BBB). The use of single chain antibodies could overcome this issue since they are smaller in size and possess higher cellular penetration capacity.

Antibodies treatment starting at the pre-symptomatic stage often proves less effective when delivered at the symptomatic stage, corroborating the need to evaluate therapeutic efficacy when the pathology has already manifested itself. As sporadic ALS patients are diagnosed only years after the beginning of their symptoms, it is unclear how such therapies could be effective.

What strikes me, is that despite the high number of studies on ALS, all the attempts to make therapies seem to explore only rather improbable paths.

Contact the author

Plasma biomarkers of inflammation and vascular injury are associated with cognitive decline.

- Posted in Plasma biomarkers of inflammation and vascular injury are associated with cognitive decline. by English by

Plasma-based biomarkers (blood tests) present a promising approach in the research and clinical practice of Alzheimer's disease as they are inexpensive, accessible and minimally invasive. enter image description here Recent studies have demonstrated the prognostic utility of plasma biomarkers of Alzheimer pathology or neurodegeneration, such as pTau-181 and NF-L, yet they do not enable to predict cognitive decline.

In this new publication, scientists conducted an observational cohort study to determine the prognostic utility of plasma biomarkers in predicting progression to dementia for individuals presenting with mild cognitive impairment due to probable Alzheimer's disease.

The scientists used an improved Elisa assay to measure the level of 460 circulating proteins in banked plasma samples of all participants. The authors used a discovery data set comprised 60 individuals with mild cognitive impairment and a validation data set consisting of 21 stable and 21 progressors.

They developed a machine learning model to distinguish progressors from stable and used 44 proteins with significantly different plasma levels in progressors versus stable along with age, sex, education and baseline cognition as candidate features.

A model with age, education, APOE genotype, baseline cognition, plasma pTau-181 and 12 plasma Olink protein biomarker levels was able to distinguish progressors from stable with 86.7% accuracy.

In the validation data set, the model accuracy was 78.6%. The Olink proteins selected by the model included those associated with vascular injury and neuroinflammation.

In addition, to compare these prognostic biomarkers to those that are altered in Alzheimer's disease or other types of dementia relative to controls, the authors analyzed samples from 20 individuals with Alzheimer, 30 with non-Alzheimer dementias and 34 with normal cognition.

The proteins NF-L and PTP-1B were significantly higher in both Alzheimer and non-Alzheimer dementias compared with cognitively normal individuals.

Interestingly, the prognostic markers of decline at the mild cognitive impairment stage did not overlap with those that differed between dementia and control cases.

In summary, authors' findings suggest that plasma biomarkers of inflammation and vascular injury are associated with cognitive decline. Developing a plasma biomarker profile could aid in prognostic deliberations and identify individuals at higher risk of dementia in clinical practice.

Are the hopes of a direct conversion of astrocytes into neurons dashed?

- Posted in Are the hopes of a direct conversion of astrocytes into neurons dashed? by English by

In 2013, Xiang-Dong Fu of the University of California, San Diego, and colleagues found that deleting a single gene converts a variety of cells, including fibroblasts, directly into neurons. This procedure represents one of the simplest methods of generating neurons to date. Since it does not require any foreign DNA, it can bring in-vivo direct cells conversion closer to the clinic.

Cellular reprogramming technology, including the generation of induced pluripotent stem cells, had raised hopes that scientists might one day replace dying cells with new ones derived from patient's healthy tissues. New presentations in 2019 had really made people think that a clinical solution for neurodegenerative diseases like Parkinson's, Alzheimer's or ALS (Charcot's disease) was at hand.

Fu's group proceeded by injecting directly into the substantia nigra of mice, an adeno-associated virus (AAV) carrying an RNA that inhibited PTBP1. To mark infected astrocytes, the vector they used included a fluorescent tag that could only be activated in cells infected with the virus (because it was under the control of the GFAP promoter). Researchers reported that fluorescent cells carrying neural markers formed connections with nearby striatum and reversed motor deficits in an animal model of Parkinson's disease. Obviously we could already be wondering why AAV viruses would only infect astrocytes, and not other cells and among these, neurons.

Indeed, several recent studies suggest that the apparently converted astrocytes would in fact have been neurons. These recent studies have used different cell lineage mapping approaches to label astrocytes. This type of lineage can be studied by marking a cell (with fluorescent molecules or other traceable markers) and following its progeny after cell division. In fact, it is a method quite similar to that used by the San Diego group.

Two of the studies, published in Cell Reports on June 14, reported that Müller's glia (a source of retinal stem cells that can replenish neuronal loss and restore vision) failed to convert into neurons when PTBP1 was deleted (Xie and al., 2022; Hoang et al., 2022). Two others – one published in Life on May 10 and the other published on bioRxiv on May 13 – came to similar conclusions with astrocytes in the substantia nigra and striatum (Chen et al., 2022; Yang et al ., 2022).

Their findings are consistent with a similar report published last year (Wang et al., 2021). Some have also found GFAP promoter expression in neurons, giving the mistaken impression that they were ancient astrocytes.

We can ask ourselves some serious questions, for example why the scientific community did not express as soon as the 2013 announcement was made, the fairly obvious fact that astrocytes were probably not the only ones to be infected, why did they wait 9 years to highlight this point?

Another question concerns the cell lines, these are different in the different studies, the cells are at different stages of maturation, and their phenotype is very different from that of astrocytes, so can we really draw general conclusions?

In addition, Müller's glia are derived from the development of two distinct populations of cells, which are we talking about in these new studies? Finally, they are the only retinal glial cells that share a common cell line with retinal neurons. From a certain point of view Müller's glia are neurons not astrocytes, and therefore this greatly diminishes the value of the analyzes carried out, but this should be known to scientists who have done these contradictory studies?

In response to these and other studies that challenge data for conversion of astrocytes to neurons, Fu recognized that some expression of the GFAP promoter occurs in neurons infected with AAV viruses. For him, about 5% of cells expressing AAV genes soon after infection were neurons. Yet this percentage seems very low.

On the other hand, Fu said that lineage tracing experiments performed in the new studies may have preferentially marked mature Müller cells, leaving open the possibility that the conversion of more immature cells into neurons may have been missed. .

Finally, knocking out PTBP1 effectively restored dopamine levels and boosted motor function in a mouse model of Parkinson's disease. If not by the creation of new neurons, what could e


Please, help us continue to provide valuable information: