GluN2A NMDA Receptor Enhancement Improves Brain Oscillations, Synchrony, and Cognitive Functions in Dravet Syndrome and Alzheimer's Disease Models.

NMDA receptors (NMDARs) play subunit-specific roles in synaptic function and are implicated in neuropsychiatric and neurodegenerative disorders. However, the in vivo consequences and therapeutic potential of pharmacologically enhancing NMDAR function via allosteric modulation are largely unknown. We examine the in vivo effects of GNE-0723, a positive allosteric modulator of GluN2A-subunit-containing NMDARs, on brain network and cognitive functions in mouse models of Dravet syndrome (DS) and Alzheimer's disease (AD). GNE-0723 use dependently potentiates synaptic NMDA receptor currents and reduces brain oscillation power with a predominant effect on low-frequency (12-20 Hz) oscillations. Interestingly, DS and AD mouse models display aberrant low-frequency oscillatory power that is tightly correlated with network hypersynchrony. GNE-0723 treatment reduces aberrant low-frequency oscillations and epileptiform discharges and improves cognitive functions in DS and AD mouse models. GluN2A-subunit-containing NMDAR enhancers may have therapeutic benefits in brain disorders with network hypersynchrony and cognitive impairments

Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia.

BACKGROUND: Genetic mutations underlying familial Alzheimer\u27s disease (AD) were identified decades ago, but the field is still in search of transformative therapies for patients. While mouse models based on overexpression of mutated transgenes have yielded key insights in mechanisms of disease, those models are subject to artifacts, including random genetic integration of the transgene, ectopic expression and non-physiological protein levels. The genetic engineering of novel mouse models using knock-in approaches addresses some of those limitations. With mounting evidence of the role played by microglia in AD, high-dimensional approaches to phenotype microglia in those models are critical to refine our understanding of the immune response in the brain. METHODS: We engineered a novel App knock-in mouse model (App RESULTS: Leveraging multi-omics approaches, we discovered profound alteration of diverse lipids and metabolites as well as an exacerbated disease-associated transcriptomic response in microglia with high intracellular Aβ content. The App DISCUSSION: Our findings demonstrate that fibrillar Aβ in microglia is associated with lipid dyshomeostasis consistent with lysosomal dysfunction and foam cell phenotypes as well as profound immuno-metabolic perturbations, opening new avenues to further investigate metabolic pathways at play in microglia responding to AD-relevant pathogenesis. The in-depth characterization of pathological hallmarks of AD in this novel and open-access mouse model should serve as a resource for the scientific community to investigate disease-relevant biology

EGFR Inhibitor Erlotinib Delays Disease Progression but Does Not Extend Survival in the SOD1 Mouse Model of ALS

<div><p></p><p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive paralysis due to motor neuron death. Several lines of published evidence suggested that inhibition of epidermal growth factor receptor (EGFR) signaling might protect neurons from degeneration. To test this hypothesis in vivo, we treated the SOD1 transgenic mouse model of ALS with erlotinib, an EGFR inhibitor clinically approved for oncology indications. Although erlotinib failed to extend ALS mouse survival it did provide a modest but significant delay in the onset of multiple behavioral measures of disease progression. However, given the lack of protection of motor neuron synapses and the lack of survival extension, the small benefits observed after erlotinib treatment appear purely symptomatic, with no modification of disease course.</p></div

Time-to-event analysis of behavior and survival.

<p>V: Vehicle; E: Erlotinib.</p

Censoring information for survival study: animal n by cause of death/euthanasia for SOD1 Tg mice.

<p>F: female; M: male.</p>*<p>mouse was above critical weight and had normal righting reflex.</p>**<p>mouse had already shown first signs of loss of righting reflex.</p

Erlotinib improves performance of SOD1 Tg mice on the balance beam.

<p>At ∼17 weeks of age, erlotinib-treated mice performed better on balance beams of 3 different sizes than vehicle-treated littermates, both for number of foot slips (A) and for latency to traverse the beam (B). Each point is the average of 3 trials per mouse. Bars represent group mean values. V – vehicle; E – erlotinib.</p

Study design and timelines.

<p>(A) Study 1: timeline for survival study. n = 106 mice (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0062342#pone-0062342-t001" target="_blank">Table 1</a> for breakdown of n per genotype and treatment) received daily IP doses of erlotinib from 5 weeks of age onwards, and their lifespan was measured. Mice were assessed in neurological exams 2 times/week between 6–9 weeks, 3 times/week from 9 weeks of age onwards, and tested on the balance beam at 17 weeks of age. (B) Study 2: timeline for histological endpoints study. Mice (n = 34; see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0062342#pone-0062342-t001" target="_blank">Table 1</a> for breakdown by genotype and treatment) were dosed from 5–9 weeks of age, and euthanized for tissue collection at 9 weeks.</p

Erlotinib alleviates disease symptoms of SOD1 Tg mice.

<p>(A) Erlotinib trends toward delay in the age of onset of weight loss. This effect approaches significance, p = 0.0527 (Wilcoxon test). (B) Erlotinib delays the age of early symptom onset (p = 0.0061, Wilcoxon test). (C) Erlotinib improves the ability of mice to perform in the wire hang test, as shown by the age at which mice were last able to hang from the wire for 60s (p = 0.0479, log-rank test). The greatest difference between treatment groups is early on (∼40–110 days), suggesting a loss of efficacy of the drug as the disease becomes more severe.</p

Animal n per treatment group in each study.

<p>Animal n per treatment group in each study.</p

Erlotinib does not change the amount of astroglial or microglial staining in SOD1 Tg spinal cord.

<p>(A) Percent area stained positive for GFAP in 9-week spinal cord. The n/group is listed at the bottom of each bar. (B) Example images (top: WT; bottom: Tg). (C) Percent area stained positive for Iba1 in 9-week spinal cord. The n/group is listed at the bottom of each bar. (D) Example images (top: WT; bottom: Tg). (E) Percent area stained positive for Iba1+ enlarged cells or Iba1+ cell clusters in 9-week spinal cord. The n/group is the same as in (A) and (C). (F) Example images. Top: Tg; bottom left: closer view of microglia in the dorsal horn; bottom right: green mask overlay of region in bottom left showing the area detected by the automated algorithm as positive for Iba1+ enlarged cells or Iba1+ cell clusters. V – vehicle; E – erlotinib.</p