Functional Analyses of Two Novel LRRK2 Pathogenic Variants in Familial Parkinson's Disease.

BACKGROUND: Pathogenic variants in the LRRK2 gene are a common monogenic cause of Parkinson's disease. However, only seven variants have been confirmed to be pathogenic. OBJECTIVES: We identified two novel LRRK2 variants (H230R and A1440P) and performed functional testing. METHODS: We transiently expressed wild-type, the two new variants, or two known pathogenic mutants (G2019S and R1441G) in HEK-293 T cells, with or without LRRK2 kinase inhibitor treatment. We characterized the phosphorylation and kinase activity of the mutants by western blotting. Thermal shift assays were performed to determine the folding and stability of the LRRK2 proteins. RESULTS: The two variants were found in two large families and segregate with the disease. They display altered LRRK2 phosphorylation and kinase activity. CONCLUSIONS: We identified two novel LRRK2 variants which segregate with the disease. The results of functional testing lead us to propose these two variants as novel causative mutations for familial Parkinson's disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Prevention of tau seeding and propagation by immunotherapy with a central tau epitope antibody.

Tauopathies are neurodegenerative diseases characterized by the intraneuronal accumulation of aggregated tau. The staging of this neurodegenerative process is well established for Alzheimer's disease as well as for other tauopathies. The stereotypical pattern of tau pathology in these diseases is consistent with the hypothesis that the tau protein can spread in a 'prion-like' manner. It proposes that extracellular pathological tau species can transmit pathology from cell to cell. Accordingly, by targeting these spreading species with therapeutic antibodies one should be able to slow or halt the progression of tau pathology. To be effective, antibodies should neutralize the pathological species present in Alzheimer's disease brains and block their cell-to-cell spread. To evaluate both aspects, tau antibody D, which recognizes an epitope in the central region of tau, and was selected for its outstanding ability to block tau seeding in cell based assays, was used in this study. Here, we addressed two fundamental questions: (i) can this anti-tau antibody neutralize the pathological species present in Alzheimer's disease brains; and (ii) can it block the cell-to-cell spread of tau seeds in vivo? First, antibody D effectively prevented the induction of tau pathology in the brains of transgenic mice that had been injected with human Alzheimer's disease brain extracts, showing that it could effectively neutralize the pathological species present in these extracts. Second, by using K18 P301L tau fibrils to induce pathology, we further demonstrated that antibody D was also capable of blocking the progression of tau pathology to distal brain regions. In contrast, an amino-terminal tau antibody, which was less effective at blocking tau seeding in vitro showed less efficacy in reducing Alzheimer's disease patient tau driven pathology in the transgenic mouse model. We did not address whether the same is true for a spectrum of other amino-terminal antibodies that were tested in vitro. These data highlight important differences between tau antibodies and, when taken together with other recently published data, suggest that epitope may be important for function.

[Personalisation in mental health: a promising way]. / La personnalisation des services de santé mentale : une voie d'avenir.

OBJECTIVES: To demonstrate the pertinence of putting personalisation at the heart of mental health services. METHODS: Review of littérature of personalisation research and intervention in the United Kingdom, the country where the personalisation is one of the key themes of the health and social services reform agenda. RESULTS: Presentation of the key challenges in the personalisation agenda and also of web tool directly inspired by research and practices in the UK. CONCLUSION: We think that individuals want to be treated as citizens that want control and choice over their destiny.

Service coordination for frail elderly individuals: an analysis of case management practices in Québec.

The objective of this article is to understand coordination as it unfolds in case management practices in the context of integrated care networks devoted to frail elderly individuals. More specifically, my goal is to describe practical coordination processes. I conducted a qualitative exploratory study using an embedded case study design. My research covers three Health and Social Services Centres in Québec. I observed that case management is more frequently justified by a situation in which home care is precarious than by the intensity and multidimensionality present in a situation. In such instances, case management intervenes through a standby mode.

[Level of evidence for case management in Alzheimer's disease: a literature review]. / Niveau de preuve de la gestion de cas dans la maladie d'Alzheimer : revue de littérature.

Alzheimer's disease or related diseases patients are particularly vulnerable to fragmentation of the French system of care and support. The government has decided to implement a national plan from which two key steps are the implementation of integration and case management. We report results of a review of the literature on both the definition of these concepts and their impacts as reported in randomized controlled studies. Important differences are noticeable between studies concerning the spectrum of integration (acute and long-term care, social and health sectors, institutional and liberal sectors and financing mode notably). Case-management has multiple sense, and it must be paid attention to intensity and context of the intervention. According to available evidence, case management is likely to improve, for the person with Alzheimer's, quality of care, quality of life and quality of life of caregivers at least. Conditions for a program to be successful are adequate targeting of the target population, sufficient level of integration and adequate intensity of case management. The programs most successful and most intensive relate an effect on prevention of loss of autonomy, even death, and no extra cost. The effects on hospitalization or entry into the institution are currently hypothetical and should be further studied.

Neuronal AMP-activated protein kinase hyper-activation induces synaptic loss by an autophagy-mediated process.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by synaptic loss that leads to the development of cognitive deficits. Synapses are neuronal structures that play a crucial role in memory formation and are known to consume most of the energy used in the brain. Interestingly, AMP-activated protein kinase (AMPK), the main intracellular energy sensor, is hyper-activated in degenerating neurons in several neurodegenerative diseases, including AD. In this context, we asked whether AMPK hyper-activation could influence synapses' integrity and function. AMPK hyper-activation in differentiated primary neurons led to a time-dependent decrease in pre- and post-synaptic markers, which was accompanied by a reduction in synapses number and a loss of neuronal networks functionality. The loss of post-synaptic proteins was mediated by an AMPK-regulated autophagy-dependent pathway. Finally, this process was also observed in vivo, where AMPK hyper-activation primed synaptic loss. Overall, our data demonstrate that during energetic stress condition, AMPK might play a fundamental role in the maintenance of synaptic integrity, at least in part through the regulation of autophagy. Thus, AMPK might represent a potential link between energetic failure and synaptic integrity in neurodegenerative conditions such as AD.

Caffeine Consumption During Pregnancy Accelerates the Development of Cognitive Deficits in Offspring in a Model of Tauopathy.

Psychoactive drugs used during pregnancy can affect the development of the brain of offspring, directly triggering neurological disorders or increasing the risk for their occurrence. Caffeine is the most widely consumed psychoactive drug, including during pregnancy. In Wild type mice, early life exposure to caffeine renders offspring more susceptible to seizures. Here, we tested the long-term consequences of early life exposure to caffeine in THY-Tau22 transgenic mice, a model of Alzheimer's disease-like Tau pathology. Caffeine exposed mutant offspring developed cognitive earlier than water treated mutants. Electrophysiological recordings of hippocampal CA1 pyramidal cells in vitro revealed that early life exposure to caffeine changed the way the glutamatergic and GABAergic drives were modified by the Tau pathology. We conclude that early-life exposure to caffeine affects the Tau phenotype and we suggest that caffeine exposure during pregnancy may constitute a risk-factor for early onset of Alzheimer's disease-like pathology.

The interdisciplinary condition of work in relational professions of the health and social care field: a theoretical standpoint.

The best-known theories on interdisciplinarity in the health and social care field seek to identify personal characteristics and organizational predispositions favourable to interprofessionnal collaboration. This paper proposes a reversal of this positioning through the theorization of interdisciplinarity in the health and social care field as a condition of the work of its professionals rather than one of their peculiar attributes. To achieve this reversal, we set out the epistemological foundations of the current debate on interdisciplinarity.

AMP-Activated Protein Kinase Is Essential for the Maintenance of Energy Levels during Synaptic Activation.

Although the brain accounts for only 2% of the total body mass, it consumes the most energy. Neuronal metabolism is tightly controlled, but it remains poorly understood how neurons meet their energy demands to sustain synaptic transmission. Here we provide evidence that AMP-activated protein kinase (AMPK) is pivotal to sustain neuronal energy levels upon synaptic activation by adapting the rate of glycolysis and mitochondrial respiration. Furthermore, this metabolic plasticity is required for the expression of immediate-early genes, synaptic plasticity, and memory formation. Important in this context, in neurodegenerative disorders such as Alzheimer disease, dysregulation of AMPK impairs the metabolic response to synaptic activation and processes that are central to neuronal plasticity. Altogether, our data provide proof of concept that AMPK is an essential player in the regulation of neuroenergetic metabolic plasticity induced in response to synaptic activation and that its deregulation might lead to cognitive impairments.

Different tau species lead to heterogeneous tau pathology propagation and misfolding.

Tauopathies are a heterogeneous group of pathologies characterized by tau aggregation inside neurons. Most of them are sporadic but certain tauopathies rely on tau gene (MAPT) mutations. They particularly differ from one to another by their different neuropathological signatures e.g. lesion shapes, regions affected and molecular composition of aggregates. Six isoforms of tau exist, but they do not all co-aggregate in each tauopathy but rather have a unique signature for each one. In some tauopathies such as Alzheimer's disease (AD), tau protein aggregation follows stereotypical anatomical stages. Recent data suggest that this progression is due to an active process of tau protein propagation from neuron-to-neuron. We wondered how tau isoforms or mutations could influence the process of tau aggregation and tau propagation. In human neuropathological material, we found that MAPT mutations induce a faster misfolding compared to tau found in sporadic AD patients. In the rat brain, we observed cell-to-cell transfer of non-pathological tau species irrespective of the tested isoform or presence of a mutation. By contrast, we found that the species of tau impact the propagation of tau pathology markers such as hyperphosphorylation and misfolding. Indeed, misfolding and hyperphosphorylated tau proteins do not spread at the same rate when tau is mutated, or the isoform composition is modified. These results clearly argue for the existence of specific folding properties of tau depending on isoforms or mutations impacting the behavior of pathological tau species.

Role of the Tau N-terminal region in microtubule stabilization revealed by new endogenous truncated forms.

Tau is a central player in Alzheimer's disease (AD) and related Tauopathies, where it is found as aggregates in degenerating neurons. Abnormal post-translational modifications, such as truncation, are likely involved in the pathological process. A major step forward in understanding the role of Tau truncation would be to identify the precise cleavage sites of the several truncated Tau fragments that are observed until now in AD brains, especially those truncated at the N-terminus, which are less characterized than those truncated at the C-terminus. Here, we optimized a proteomics approach and succeeded in identifying a number of new N-terminally truncated Tau species from the human brain. We initiated cell-based functional studies by analyzing the biochemical characteristics of two N-terminally truncated Tau species starting at residues Met11 and Gln124 respectively. Our results show, interestingly, that the Gln124-Tau fragment displays a stronger ability to bind and stabilize microtubules, suggesting that the Tau N-terminal domain could play a direct role in the regulation of microtubule stabilization. Future studies based on our new N-terminally truncated-Tau species should improve our knowledge of the role of truncation in Tau biology as well as in the AD pathological process.

Beneficial effects of caffeine in a transgenic model of Alzheimer's disease-like tau pathology.

Tau pathology found in Alzheimer's disease (AD) is crucial in cognitive decline. Epidemiologic evidences support that habitual caffeine intake prevents memory decline during aging and reduces the risk to develop Alzheimer's disease. So far, experimental studies addressed the impact of caffeine in models mimicking the amyloid pathology of AD. However, in vivo effects of caffeine in a model of AD-like tauopathy remain unknown. Here, we evaluated effects of chronic caffeine intake (0.3 g/L through drinking water), given at an early pathologic stage, in the THY-Tau22 transgenic mouse model of progressive AD-like tau pathology. We found that chronic caffeine intake prevents from the development of spatial memory deficits in tau mice. Improved memory was associated with reduced hippocampal tau phosphorylation and proteolytic fragments. Moreover, caffeine treatment mitigated several proinflammatory and oxidative stress markers found upregulated in the hippocampus of THY-Tau22 animals. Together, our data support that moderate caffeine intake is beneficial in a model of AD-like tau pathology, paving the way for future clinical evaluation in AD patients.

Neuron-to-neuron wild-type Tau protein transfer through a trans-synaptic mechanism: relevance to sporadic tauopathies.

BACKGROUND: In sporadic Tauopathies, neurofibrillary degeneration (NFD) is characterised by the intraneuronal aggregation of wild-type Tau proteins. In the human brain, the hierarchical pathways of this neurodegeneration have been well established in Alzheimer's disease (AD) and other sporadic tauopathies such as argyrophilic grain disorder and progressive supranuclear palsy but the molecular and cellular mechanisms supporting this progression are yet not known. These pathways appear to be associated with the intercellular transmission of pathology, as recently suggested in Tau transgenic mice. However, these conclusions remain ill-defined due to a lack of toxicity data and difficulties associated with the use of mutant Tau. RESULTS: Using a lentiviral-mediated rat model of hippocampal NFD, we demonstrated that wild-type human Tau protein is axonally transferred from ventral hippocampus neurons to connected secondary neurons even at distant brain areas such as olfactory and limbic systems indicating a trans-synaptic protein transfer. Using different immunological tools to follow phospho-Tau species, it was clear that Tau pathology generated using mutated Tau remains near the IS whereas it spreads much further using the wild-type one. CONCLUSION: Taken together, these results support a novel mechanism for Tau protein transfer compared to previous reports based on transgenic models with mutant cDNA. It also demonstrates that mutant Tau proteins are not suitable for the development of experimental models helpful to validate therapeutic intervention interfering with Tau spreading.

Ectosomes: a new mechanism for non-exosomal secretion of tau protein.

Tau is a microtubule-associated protein that aggregates in neurodegenerative disorders known as tauopathies. Recently, studies have suggested that Tau may be secreted and play a role in neural network signalling. However, once deregulated, secreted Tau may also participate in the spreading of Tau pathology in hierarchical pathways of neurodegeneration. The mechanisms underlying neuron-to-neuron Tau transfer are still unknown; given the known role of extra-cellular vesicles in cell-to-cell communication, we wondered whether these vesicles could carry secreted Tau. We found, among vesicles, that Tau is predominately secreted in ectosomes, which are plasma membrane-originating vesicles, and when it accumulates, the exosomal pathway is activated.

[Coordination in case management practices in the context of integrated home care networks devoted to the frail elderly, a qualitative exploratory analysis]. / Les pratiques de coordination en gestion de cas dans le secteur du soutien à domicile pour les personnes en perte d'autonomie liée au vieillissement, une analyse conventionnaliste.

The objective of this article is to understand coordination as it unfolds in case management practices in the context of integrated care networks devoted to frail elderly individuals. More specifically, we describe practical coordination processes. We conducted a qualitative exploratory study using an embedded case study design. Our study covers three health and social service centers in Québec. We noted that coordination produces convention in case management practices through a process of bringing together different types of compromise in home care situations where multidimensionality appears to be more or less important. We constructed four different types of compromise-producing convention with regard to coordination in case management practices: compromise at the interface, scheduling compromise, compromise of opportunity, and compromising change.