Biology subjects

Hemonnot-Girard, A.-L.

Publications and source records attributed to Hemonnot-Girard, A.-L..

2 recordsLinked to original sources

bioRxiv2026

APPNL-F knock-in Alzheimer's Disease model mice reveal etiological convergence of aging and amyloidosis

Alzheimers disease (AD) is the leading cause of dementia worldwide, with a steadily increasing prevalence. Despite the advent of some plaque-degrading therapies, early intervention strategies are still suboptimal, largely due to an incomplete understanding of how early pathological events of amyloid-{beta} (A{beta}) plaque deposition entail or accompany the neuroinflammatory processes that ensue. The APPNL-F mouse line is a second-generation endogenous-promoter knock-in AD model that represents a valuable tool to dissect disease mechanisms and evaluate therapeutic strategies. However, the early prodromal stage remains poorly characterized. Here we performed in-depth analyses in both homozygous (APPNL-F/NL-F) and heterozygous (APPNL-F/WT) mice at 3, 6, 9 and 12 months of age. Among a battery of behavioural tests, the first phenotype was observed at 9 months with defects in spatial memory. Using hypersensitive MSD-ELISA technology assays we quantified distinct A{beta} species and found that A{beta}42 oligomers, protofibrils, and fibrillar aggregates were detectable as early as 6 months of age in homozygous APPNL-F/NL-F mice. By 9 months, their A{beta}42 levels increased markedly and overt A{beta} plaques were detected, histologically associated with recruited glial cells. Targeted RT-qPCR analysis of neuroinflammation-related genes in the cortex also identified 9 months as a molecular tipping point in these middle aged APPNL-F mice. To characterize the etiological signal transduction at the cellular level, we isolated microglia, the brain resident immune cells, whose contribution to AD pathogenesis is now well established. Sequencing around 5,000 individual cells from both 12-month-old APPNL-F/NL-F and APPWT/WT CD11b+ myeloid cells revealed that the buildup of amyloidosis was associated with an accelerated shift of microglia from a homeostatic toward a senescent-like state. Together, these findings highlight the 6-12 month period of the APPNL-F/NL-F model as a powerful system to study the interdependence between microglial senescence and amyloidosis in driving AD progression.

neuroscience↗

bioRxiv2020

Restoring Glutamate receptosome dynamics at synapses rescues Autism-like deficits in Shank3-deficient mice.

Shank3 monogenic mutations lead to Autism Spectrum Disorders (ASD). Shank3 is part of the glutamate receptosome that physically links ionotropic NMDA receptors to metabotropic mGlu5 receptors through interactions with scaffolding proteins PSD95-GKAP-Shank3-Homer. A main physiological function of the glutamate receptosome is to control NMDA synaptic function that is required for plasticity induction. Intact glutamate receptosome supports glutamate receptors activation and plasticity induction, while glutamate receptosome disruption blocks receptors activity, preventing the induction of subsequent plasticity. Despite possible impact on metaplasticity and cognitive behaviors, scaffold interaction dynamics and their consequences are poorly defined. Here we used mGlu5-Homer interaction as a biosensor of glutamate receptosome integrity to report changes of NMDA synaptic function. Combining BRET imaging and electrophysiology, we show that a transient neuronal depolarization inducing NMDA-dependent plasticity disrupts glutamate receptosome in a long-lasting manner at synapses and induces signaling required for the expression of the initiated neuronal plasticity such as ERK and mTOR pathways. Glutamate receptosome disruption also decreases NMDA/AMPA currents ratio, freezing the sensitivity of the synapse to subsequent changes of neuronal activity. These data show the importance of a fine-tuning of protein-protein interactions within glutamate receptosome, driven by changes of neuronal activity, to control plasticity. In a mouse model of ASD, a truncated mutant form of Shank3 prevents the integrity of the glutamate receptosome. These mice display altered plasticity, anxiety-like and stereotyped behaviors. Interestingly, repairing the integrity of glutamate receptosome and its sensitivity to the neuronal activity rescued synaptic transmission, plasticity and some behavioral traits of Shank3{triangleup}C mice. Altogether, our findings characterize mechanisms by which Shank3 mutations cause ASD and highlight scaffold dynamics as new therapeutic target.

neuroscience↗