Increase in Tau Pathology in P290S Mapt Knock-In Mice Crossed with AppNL-G-F Mice

Alzheimer's Disease (AD) is characterized by the pathological assembly of Aβ peptide, which deposits into extracellular plaques, and tau, which accumulates in intraneuronal inclusions. To investigate the link between Aβ and tau pathologies, experimental models featuring both pathologies are needed. We developed a mouse model featuring both tau and Aβ pathologies by knocking the P290S mutation into murine Mapt and crossing these MaptP290S KI mice with the AppNL-G-F KI line. MaptP290S KI mice developed a small number of tau inclusions, which increased with age. The amount of tau pathology was significantly larger in AppNL-G-FxMaptP290S KI mice from 18-months of age onwards. Tau pathology was higher in limbic areas, including hippocampus, amygdala and piriform/entorhinal cortex. We also observed AT100-and Gallyas-Braak-silver-positive dystrophic neurites containing assembled filamentous tau, as visualized by in situ EM. Using a cell-based tau seeding assay, we showed that sarkosyl-insoluble brain extracts from both 18-month-old MaptP290S KI and AppNL-G-FxMaptP290S KI mice were seed-competent, with brain extracts from double KI mice seeding significantly more than those from the MaptP290S KI mice. Finally, we showed that AppNL-G-FxMaptP290S KI mice had neurodegeneration in the piriform cortex from 18-months of age. We suggest that AppNL-G-F x MaptP290S KI mice provide a good model for studying the interactions of aggregation-prone tau, Aβ, neuritic plaques, neurodegeneration and aging

Assembly of alpha-synuclein and neurodegeneration in the central nervous system of heterozygous M83 mice following the peripheral administration of alpha-synuclein seeds

Peripheral administration (oral, intranasal, intraperitoneal, intravenous) of assembled A53T α-synuclein induced synucleinopathy in heterozygous mice transgenic for human mutant A53T α-synuclein (line M83). The same was the case when cerebellar extracts from a case of multiple system atrophy with type II α-synuclein filaments were administered intraperitoneally, intravenously or intramuscularly. We observed abundant immunoreactivity for pS129 α-synuclein in nerve cells and severe motor impairment, resulting in hindlimb paralysis and shortened lifespan. Filaments immunoreactive for pS129 α-synuclein were in evidence. A 70% loss of motor neurons was present five months after an intraperitoneal injection of assembled A53T α-synuclein or cerebellar extract with type II α-synuclein filaments from an individual with a neuropathologically confirmed diagnosis of multiple system atrophy. Microglial cells changed from a predominantly ramified to a dystrophic appearance. Taken together, these findings establish a close relationship between the formation of α-synuclein inclusions in nerve cells and neurodegeneration, accompanied by a shift in microglial cell morphology. Propagation of α-synuclein inclusions depended on the characteristics of both seeds and transgenically expressed protein

Development of broad-spectrum human monoclonal antibodies for rabies post-exposure prophylaxis

Currently available rabies post-exposure prophylaxis (PEP) for use in humans includes equine or human rabies immunoglobulins (RIG). The replacement of RIG with an equally or more potent and safer product is strongly encouraged due to the high costs and limited availability of existing RIG. In this study, we identified two broadly neutralizing human monoclonal antibodies that represent a valid and affordable alternative to RIG in rabies PEP. Memory B cells from four selected vaccinated donors were immortalized and monoclonal antibodies were tested for neutralizing activity and epitope specificity. Two antibodies, identified as RVC20 and RVC58 (binding to antigenic site I and III, respectively), were selected for their potency and broad-spectrum reactivity. In vitro, RVC20 and RVC58 were able to neutralize all 35 rabies virus (RABV) and 25 non-RABV lyssaviruses. They showed higher potency and breath compared to antibodies under clinical development (namely CR57, CR4098, and RAB1) and commercially available human RIG. In vivo, the RVC20-RVC58 cocktail protected Syrian hamsters from a lethal RABV challenge and did not affect the endogenous hamster post-vaccination antibody response

The French Integrative Psychosocial Rehabilitation Assessment for Complex Situations (FIPRACS): Modelization of an Adapted Assessment Method Toward Long-Term Psychiatric Inpatients With Disabling, Severe and Persistent Mental Illness

For the past forty years, the generalization of community-based approaches has prompted psychiatry into promoting a deinstitutionalization movement and a psychosocial rehabilitation approach (PSR) for individuals with schizophrenia and related difficulties. Unfortunately, this approach generally does not involve the most severe cognitive and psycho-affective clinical situations among this population despite an increasing number of publications advocating that all individuals should be included in PSR and deinstitutionalization programs. In this context, considering the absence of an assessment battery designed for French individuals with particularly disabling, severe, and persistent mental illness (IDSPMI), we constructed an integrative assessment model adapted to this specific population. To select the most suitable tools for this population, a literature review (inspired by the PRISMA protocol) and a systematic review were combined with a clinical assessment study. The literature review first identified the cognitive and psycho-affective functions which mainly influence the day-to-day life adaptation of individuals engaged in a PSR/deinstitutionalization program. The systematic review then gathered all of the useable French validated tools to assess the initially selected dimensions (n = 87). To finish, for each dimension, the selected 87 tools were included in a clinical assessment study performed within a French psychiatric hospital. The authors collected and verified the characteristics of each tool (validity, French norms, French version, the average speed of the test, ease of use, ability to assess other dimensions). Their suitability was also assessed when applied to IDSPMI. Based on this final clinical evaluation, the authors selected one tool per function to create the French Integrative Psychosocial Rehabilitation Assessment for Complex Situations (FIPRACS). This battery is an assessment tailored to the neurocognitive and psycho-affective potentials of IDSPMI. While further validation studies of this battery are ultimately required, the practical/clinical implications of this battery are presented and discussed.</p

Chromosomal translocations and leukaemia : a role for LMO2 in T cell acute leukaemia, in transcription and in erythropoiesis

The LMO2 gene associated with T cell acute leukaemia has been used as an example of a gene activated by association with the T cell receptor genes after chromosomal translocations. The gene is shown to encode a LIM protein which is involved in protein interactions and during normal haematopoiesis is necessary for erythroid development. LMO2 has been shown to cause tumours when aberrantly expressed and to be able to heterodimerise with TAL1 to facilitate tumour development