Tau seeds from Alzheimer's disease brains trigger tau spread in macaques while oligomeric-Aß mediates pathology maturation.

INTRODUCTION: The "prion-like" features of Alzheimer's disease (AD) tauopathy and its relationship with amyloid-ß (Aß) have never been experimentally studied in primates phylogenetically close to humans. METHODS: We injected 17 macaques in the entorhinal cortex with nanograms of seeding-competent tau aggregates purified from AD brains or control extracts from aged-matched healthy brains, with or without intracerebroventricular co-injections of oligomeric-Aß. RESULTS: Pathological tau injection increased cerebrospinal fluid (CSF) p-tau181 concentration after 18 months. Tau pathology spreads from the entorhinal cortex to the hippocampal trisynaptic loop and the cingulate cortex, resuming the experimental progression of Braak stage I to IV. Many AD-related molecular networks were impacted by tau seeds injections regardless of Aß injections in proteomic analyses. However, we found mature neurofibrillary tangles, increased CSF total-tau concentration, and pre- and postsynaptic degeneration only in Aß co-injected macaques. DISCUSSION: Oligomeric-Aß mediates the maturation of tau pathology and its neuronal toxicity in macaques but not its initial spreading. HIGHLIGHTS: This study supports the "prion-like" properties of misfolded tau extracted from AD brains. This study empirically validates the Braak staging in an anthropomorphic brain. This study highlights the role of oligomeric Aß in driving the maturation and toxicity of tau pathology. This work establishes a novel animal model of early sporadic AD that is closer to the human pathology.

Impact of dietary vitamin A on striatal function in adult rats.

The striatum is a brain structure involved in the control of voluntary movement. Striatum contains high amounts of retinoic acid, the active metabolite of vitamin A, as well as retinoid receptors, RARß and RXRγ. Previous studies revealed that disruption of retinoid signaling initiated during development is deleterious for striatal physiology and related motor functions. However, the alteration of retinoid signaling, and the importance of vitamin A supply during adulthood on striatal physiology and function has never been established. In the present study, we investigated the impact of vitamin A supply on striatal function. Adult Sprague-Dawley rats were fed with three specific diets, either sub-deficient, sufficient, or enriched in vitamin A (0.4, 5, and 20 international units [IU] of retinol per g of diet, respectively) for 6 months. We first validated that vitamin A sub-deficient diet in adult rats constitutes a physiological model of retinoid signaling reduction in the striatum. We then revealed subtle alterations of fine motor skills in sub-deficient rats using a new behavioral apparatus specifically designed to test forepaw reach-and-grasp skills relying on striatal function. Finally, we showed using qPCR analysis and immunofluorescence that the striatal dopaminergic system per se was not affected by vitamin A sub-deficiency at adult age. Rather, cholinergic synthesis in the striatum and µ-opioid receptor expression in striosomes sub-territories were the most affected by vitamin A sub-deficiency starting at adulthood. Taken together these results revealed that retinoid signaling alteration at adulthood is associated with motor learning deficits together with discrete neurobiological alterations in the striatum.

Pathogenic Aspects and Therapeutic Avenues of Autophagy in Parkinson's Disease.

The progressive aging of the population and the fact that Parkinson's disease currently does not have any curative treatment turn out to be essential issues in the following years, where research has to play a critical role in developing therapy. Understanding this neurodegenerative disorder keeps advancing, proving the discovery of new pathogenesis-related genes through genome-wide association analysis. Furthermore, the understanding of its close link with the disruption of autophagy mechanisms in the last few years permits the elaboration of new animal models mimicking, through multiple pathways, different aspects of autophagic dysregulation, with the presence of pathological hallmarks, in brain regions affected by Parkinson's disease. The synergic advances in these fields permit the elaboration of multiple therapeutic strategies for restoring autophagy activity. This review discusses the features of Parkinson's disease, the autophagy mechanisms and their involvement in pathogenesis, and the current methods to correct this cellular pathway, from the development of animal models to the potentially curative treatments in the preclinical and clinical phase studies, which are the hope for patients who do not currently have any curative treatment.

Modulating Lysosomal pH through Innovative Multimerized Succinic Acid-Based Nucleolipid Derivatives.

The multimerization of active compounds has emerged as a successful approach, mainly to address the multivalency of numerous biological targets. Regarding the pharmaceutical prospect, carrying several active ingredient units on the same synthetic scaffold was a practical approach to enhance drug delivery or biological activity with a lower global concentration. Various examples have highlighted better in vivo stability and therapeutic efficiency through sustained action over monomeric molecules. The synthesis strategy aims to covalently connect biologically active monomers to a central core using simple and efficient reaction steps. Despite extensive studies reporting carbohydrate or even peptide multimerization developed for therapeutic activities, very few are concerned with nucleic acid derivatives. In the context of our efforts to build non-viral nucleolipid (NL)-based nanocarriers to restore lysosomal acidification defects, we report here a straightforward synthesis of tetrameric NLs, designed as prodrugs that are able to release no more than one but four biocompatible succinic acid units. The use of oil-in-water nanoemulsion-type vehicles allowed the development of lipid nanosystems crossing the membranes of human neuroblastoma cells. Biological evaluations have proved the effective release of the acid within the lysosome of a genetic and cellular model of Parkinson's disease through the recovery of an optimal lysosomal pH associated with a remarkably fourfold lower concentration of active ingredients than with the corresponding monomers. Overall, these results suggest the feasibility, the therapeutic opportunity, and the better tolerance of multimeric compounds compared to only monomer molecules.