In Vivo Imaging Biomarkers in Mouse Models of Alzheimer's Disease: Are We Lost in Translation or Breaking Through?

Identification of biomarkers of Alzheimer's Disease (AD) is a critical priority to efficiently diagnose the patients, to stage the progression of neurodegeneration in living subjects, and to assess the effects of disease-modifier treatments. This paper addresses the development and usefulness of preclinical neuroimaging biomarkers of AD. It is today possible to image in vivo the brain of small rodents at high resolution and to detect the occurrence of macroscopic/microscopic lesions in these species, as well as of functional alterations reminiscent of AD pathology. We will outline three different types of imaging biomarkers that can be used in AD mouse models: biomarkers with clear translational potential, biomarkers that can serve as in vivo readouts (in particular in the context of drug discovery) exclusively for preclinical research, and finally biomarkers that constitute new tools for fundamental research on AD physiopathogeny

Transmission of amyloid lesions in Alzheimer’s disease: contributing data from animal models

Depuis la découverte du caractère transmissible des maladies à prions, d’autres protéinopathies cérébrales ont été soupçonnées d’être similairement transmissibles. La maladie d’Alzheimer (MA) est caractérisée par des dépôts cérébraux de peptides (Aβ ) et de protéines Tau hyperphosphorylées, respectivement en plaques amyloïdes et dégénérescences neurofibrillaires. Bien qu’aucune étude épidémiologique ne montre que la MA se transmette entre individus, plusieurs études ont récemment soulevé des soupçons de transmission iatrogène des dépôts β-amyloïdes chez l’Homme. Elles suggèrent que le changement de conformation (ou mépliement) de l’Aβ et son agrégation se produit par des mécanismes de nucléation-élongation et de propagation, similaires à ceux décrits pour les maladies à prions. Ici, nous présentons une revue de la littérature démontrant à partir d’études in vivo la pertinence des mécanismes de mépliement et agrégation de type prion pour la pathologie β-amyloïde.Since the discovery of the transmissibility of prion diseases, other cerebral proteinopathies have been suspected to harbor similar transmissible properties. Alzheimer’s disease (AD) is characterized by the deposition of misfolded β-amyloïdes (Aβ ) peptides and hyperphosphorylated Tau proteins, forming amyloid plaques and neurofibrillary tangles respectively in the brain. Although available epidemiological data suggest that AD is not transmitted between individuals, suspicion has recently been raised for iatrogenic β-amyloidosis transmission between humans. This suggests that A b misfolding and aggregation could occur through seeding and spreading mechanisms, virtually identical to those of prions. Here, we present a review of the literature focusing on the relevance of prion-like misfolding and aggregation mechanisms for Aβ in animal models

Balloon test project: Cosmic Ray Antimatter Calorimeter (CRAC)

Cosmic ray observations from balloon flights are discussed. The cosmic ray antimatter calorimeter (CRAC) experiment attempts to measure the flux of antimatter in the 200-600 Mev/m energy range and the isotopes of light elements between 600 and 1,000 Mev/m

An evolutionary gap in primate default mode network organization

The human default mode network (DMN) is engaged at rest and in cognitive states such as self-directed thoughts. Interconnected homologous cortical areas in primates constitute a network considered as the equivalent. Here, based on a cross-species comparison of the DMN between humans and non-hominoid primates (macaques, marmosets, and mouse lemurs), we report major dissimilarities in connectivity profiles. Most importantly, the medial prefrontal cortex (mPFC) of non-hominoid primates is poorly engaged with the posterior cingulate cortex (PCC), though strong correlated activity between the human PCC and the mPFC is a key feature of the human DMN. Instead, a fronto-temporal resting-state network involving the mPFC was detected consistently across non-hominoid primate species. These common functional features shared between non-hominoid primates but not with humans suggest a substantial gap in the organization of the primate\u27s DMN and its associated cognitive functions

The JAK/STAT3 Pathway Is a Common Inducer of Astrocyte Reactivity in Alzheimer's and Huntington's Diseases.

Astrocyte reactivity is a hallmark of neurodegenerative diseases (ND), but its effects on disease outcomes remain highly debated. Elucidation of the signaling cascades inducing reactivity in astrocytes during ND would help characterize the function of these cells and identify novel molecular targets to modulate disease progression. The Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway is associated with reactive astrocytes in models of acute injury, but it is unknown whether this pathway is directly responsible for astrocyte reactivity in progressive pathological conditions such as ND. In this study, we examined whether the JAK/STAT3 pathway promotes astrocyte reactivity in several animal models of ND. The JAK/STAT3 pathway was activated in reactive astrocytes in two transgenic mouse models of Alzheimer's disease and in a mouse and a nonhuman primate lentiviral vector-based model of Huntington's disease (HD). To determine whether this cascade was instrumental for astrocyte reactivity, we used a lentiviral vector that specifically targets astrocytes in vivo to overexpress the endogenous inhibitor of the JAK/STAT3 pathway [suppressor of cytokine signaling 3 (SOCS3)]. SOCS3 significantly inhibited this pathway in astrocytes, prevented astrocyte reactivity, and decreased microglial activation in models of both diseases. Inhibition of the JAK/STAT3 pathway within reactive astrocytes also increased the number of huntingtin aggregates, a neuropathological hallmark of HD, but did not influence neuronal death. Our data demonstrate that the JAK/STAT3 pathway is a common mediator of astrocyte reactivity that is highly conserved between disease states, species, and brain regions. This universal signaling cascade represents a potent target to study the role of reactive astrocytes in ND