Sustained correction of hippocampal neurogenic and cognitive deficits after a brief treatment by Nutlin-3 in a mouse model of Fragile X Syndrome

Background: Fragile X syndrome (FXS), the most prevalent inherited intellectual disability and one of the most common monogenic form of autism, is caused by a loss of FMRP translational regulator 1 (FMR1). We have previously shown that FMR1 represses the levels and activities of ubiquitin ligase MDM2 in young adult FMR1-deficient mice and treatment by a MDM2 inhibitor Nutlin-3 rescues both hippocampal neurogenic and cognitive deficits in FMR1-deficient mice when analyzed shortly after the administration. However, it is unknown whether Nutlin-3 treatment can have long-lasting therapeutic effects. Methods: We treated 2-month-old young adult FMR1-deficient mice with Nutlin-3 for 10 days and then assessed the persistent effect of Nutlin-3 on both cognitive functions and adult neurogenesis when mice were 6-month-old mature adults. To investigate the mechanisms underlying persistent effects of Nutlin-3, we analyzed proliferation and differentiation of neural stem cells isolated from these mice and assessed the transcriptome of the hippocampal tissues of treated mice. Results: We found that transient treatment with Nutlin-3 of 2-month-old young adult FMR1-deficient mice prevents the emergence of neurogenic and cognitive deficits in mature adult FXS mice at 6-month of age. We further found that the long-lasting restoration of neurogenesis and cognitive function might not be mediated by changing intrinsic properties of adult neural stem cells. Transcriptomic analysis of the hippocampal tissue demonstrated that transient Nultin-3 treatment leads to significant expression changes in genes related to extracellular matrix, secreted factors, and cell membrane proteins in FMR1-deficient hippocampus.

Abnormal lipid droplets accumulation induced cognitive deficits in obstructive sleep apnea syndrome mice via JNK/SREBP/ACC pathway but not through PDP1/PDC pathway

The mechanisms of chronic intermittent hypoxia (CIH)-induced cognitive deficits remain unclear. Here, our study found that about 3 months CIH treatment induced lipid droplets (LDs) accumulation in hippocampal nerve and glia cells of C57BL/6 mice, and caused severe neuro damage including neuron lesions, neuroblast (NB) apoptosis and abnormal glial activation. Studies have shown that the neuronal metabolism disorders might contribute to the CIH induced-hippocampal impairment. Mechanistically, the results showed that pyruvate dehydrogenase complex E1ɑ subunit (PDHA1) and the pyruvate dehydrogenase complex (PDC) activator pyruvate dehydrogenase phosphatase 1 (PDP1) did not noticeable change after intermittent hypoxia. Consistent with those results, the level of Acetyl-CoA in hippocampus did not significantly change after CIH exposure. Interestingly, we found that CIH produced large quantities of ROS, which activated the JNK/SREBP/ACC pathway in nerve and glia cells. ACC catalyzed the carboxylation of Acetyl-CoA to malonyl-CoA and then more lipid acids were synthesized, which finally caused aberrant LDs accumulation. Therefore, the JNK/SREBP/ACC pathway played a crucial role in the cognitive deficits caused by LDs accumulation after CIH exposure. Additionally, LDs were peroxidized by the high level of ROS under CIH conditions. Together, lipid metabolic disorders contributed to nerve and glia cells damage, which ultimately caused behavioral dysfunction. An active component of Salvia miltiorrhiza, SMND-309, dramatically alleviated these injuries and improved cognitive deficits of CIH mice.

Improvements in Cognitive Function and Quantitative Sleep EEG in OSA after Six Months of CPAP Treatment

Study Objectives Untreated obstructive sleep apnea (OSA) is associated with cognitive deficits and altered brain electrophysiology. We evaluated the effect of continuous positive airway pressure (CPAP) treatment on quantitative sleep electroencephalogram (EEG) measures and cognitive function. Methods We studied 162 OSA patients (age 50±13, AHI 35.0±26.8) before and after 6 months of CPAP. Cognitive tests assessed working memory, sustained attention, visuospatial scanning and executive function. All participants underwent overnight polysomnography at baseline and after CPAP. Power spectral analysis was performed on EEG data (C3-M2) in a sub-set of 90 participants. Relative delta EEG power and sigma power in NREM and EEG slowing in REM were calculated. Spindle densities (events p/min) in N2 were also derived using automated spindle event detection. All outcomes were analysed as change from baseline. Results Cognitive function across all cognitive domains improved after six months of CPAP. In our sub-set, increased relative delta power (p<0.0001) and reduced sigma power (p=0.001) during NREM were observed after the 6-month treatment period. Overall, fast and slow sleep spindle densities during N2 were increased after treatment. Conclusions Cognitive performance was improved and sleep EEG features were enhanced when assessing the effects of CPAP. These findings suggest the reversibility of cognitive deficits and altered brain electrophysiology observed in untreated OSA following six months of treatment.

G-quadruplexes Stabilization Upregulates CCN1 and Accelerates Aging in Cultured Cerebral Endothelial Cells

Senescence in the cerebral endothelium has been proposed as a mechanism that can drive dysfunction of the cerebral vasculature, which precedes vascular dementia. Cysteine-rich angiogenic inducer 61 (Cyr61/CCN1) is a matricellular protein secreted by cerebral endothelial cells (CEC). CCN1 induces senescence in fibroblasts. However, whether CCN1 contributes to senescence in CEC and how this is regulated requires further study. Aging has been associated with the formation of four-stranded Guanine-quadruplexes (G4s) in G-rich motifs of DNA and RNA. Stabilization of the G4 structures regulates transcription and translation either by upregulation or downregulation depending on the gene target. Previously, we showed that aged mice treated with a G4-stabilizing compound had enhanced senescence-associated (SA) phenotypes in their brains, and these mice exhibited enhanced cognitive deficits. A sequence in the 3′-UTR of the human CCN1 mRNA has the ability to fold into G4s in vitro. We hypothesize that G4 stabilization regulates CCN1 in cultured primary CEC and induces endothelial senescence. We used cerebral microvessel fractions and cultured primary CEC from young (4-months old, m/o) and aged (18-m/o) mice to determine CCN1 levels. SA phenotypes were determined by high-resolution fluorescence microscopy in cultured primary CEC, and we used Thioflavin T to recognize RNA-G4s for fluorescence spectra. We found that cultured CEC from aged mice exhibited enhanced levels of SA phenotypes, and higher levels of CCN1 and G4 stabilization. In cultured CEC, CCN1 induced SA phenotypes, such as SA β-galactosidase activity, and double-strand DNA damage. Furthermore, CCN1 levels were upregulated by a G4 ligand, and a G-rich motif in the 3′-UTR of the Ccn1 mRNA was folded into a G4. In conclusion, we demonstrate that CCN1 can induce senescence in cultured primary CEC, and we provide evidence that G4 stabilization is a novel mechanism regulating the SASP component CCN1.

Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology

Alzheimer’s disease (AD) alters astrocytes, but the effect of Aß and Tau pathology is poorly understood. TRAP-seq translatome analysis of astrocytes in APP/PS1 ß-amyloidopathy and MAPTP301S tauopathy mice revealed that only Aß influenced expression of AD risk genes, but both pathologies precociously induced age-dependent changes, and had distinct but overlapping signatures found in human post-mortem AD astrocytes. Both Aß and Tau pathology induced an astrocyte signature involving repression of bioenergetic and translation machinery, and induction of inflammation pathways plus protein degradation/proteostasis genes, the latter enriched in targets of inflammatory mediator Spi1 and stress-activated cytoprotective Nrf2. Astrocyte-specific Nrf2 expression induced a reactive phenotype which recapitulated elements of this proteostasis signature, reduced Aß deposition and phospho-tau accumulation in their respective models, and rescued brain-wide transcriptional deregulation, cellular pathology, neurodegeneration and behavioural/cognitive deficits. Thus, Aß and Tau induce overlapping astrocyte profiles associated with both deleterious and adaptive-protective signals, the latter of which can slow patho-progression.

Differential associations between neocortical tau pathology and blood flow with cognitive deficits in early-onset vs late-onset Alzheimer’s disease

Purpose Early-onset Alzheimer’s disease (EOAD) and late-onset Alzheimer’s disease (LOAD) differ in neuropathological burden and type of cognitive deficits. Assessing tau pathology and relative cerebral blood flow (rCBF) measured with [18F]flortaucipir PET in relation to cognition may help explain these differences between EOAD and LOAD. Methods Seventy-nine amyloid-positive individuals with a clinical diagnosis of AD (EOAD: n = 35, age-at-PET = 59 ± 5, MMSE = 23 ± 4; LOAD: n = 44, age-at-PET = 71 ± 5, MMSE = 23 ± 4) underwent a 130-min dynamic [18F]flortaucipir PET scan and extensive neuropsychological assessment. We extracted binding potentials (BPND) and R1 (proxy of rCBF) from parametric images using receptor parametric mapping, in medial and lateral temporal, parietal, occipital, and frontal regions-of-interest and used nine neuropsychological tests covering memory, attention, language, and executive functioning. We first examined differences between EOAD and LOAD in BPND or R1 using ANOVA (region-of-interest analysis) and voxel-wise contrasts. Next, we performed linear regression models to test for potential interaction effects between age-at-onset and BPND/R1 on cognition. Results Both region-of-interest and voxel-wise contrasts showed higher [18F]flortaucipir BPND values across all neocortical regions in EOAD. By contrast, LOAD patients had lower R1 values (indicative of more reduced rCBF) in medial temporal regions. For both tau and flow in lateral temporal, and occipitoparietal regions, associations with cognitive impairment were stronger in EOAD than in LOAD (EOAD BPND − 0.76 ≤ stβ ≤ − 0.48 vs LOAD − 0.18 ≤ stβ ≤ − 0.02; EOAD R1 0.37 ≤ stβ ≤ 0.84 vs LOAD − 0.25 ≤ stβ ≤ 0.16). Conclusions Compared to LOAD, the degree of lateral temporal and occipitoparietal tau pathology and relative cerebral blood-flow is more strongly associated with cognition in EOAD.