Effects of α5 GABAA receptor modulation on social interaction,memory, and neuroinflammation in a mouse model of Alzheimer's disease

AimsGABAergic modulation involved in cognitive processing appears to be substantially changed in Alzheimer''s disease (AD). In a widely used 5xFAD model of AD, we aimed to assess if negative and positive allosteric modulators of α5 GABA_A receptors (NAM and PAM, respectively) would affect social interaction, social, object and spatial memory, and neuroinflammation.MethodsAfter 10‐day treatment with PAM, NAM, or solvent, 6‐month‐old transgenic and non‐transgenic 5xFAD mice underwent testing in a behavioral battery. Gene expressions of IL‐1β, IL‐6, TNF‐α, GFAP, and IBA‐1 were determined in hippocampus and prefrontal cortex by qPCR.ResultsPAM treatment impaired spatial learning in transgenic females compared to solvent‐treated transgenic females, and social recognition in transgenic and non‐transgenic males. NAM treatment declined social interaction in transgenic and non‐transgenic males, while had beneficial effect on cognitive flexibility in non‐transgenic males compared to solvent‐treated non‐transgenic males. Transgenic animals have not fully displayed cognitive symptoms, but neuroinflammation was confirmed. NAM reduced proinflammatory gene expressions in transgenic females and astrogliosis in transgenic males compared to pathological controls.ConclusionPAM and NAM failed to exert favorable behavioral effects in transgenic animals. Suppression of neuroinflammation obtained with NAM calls for more studies with GABAergic ligands in amyloid beta‐ and/or tau‐dependent models with prominent neuroinflammation.     

When the microbiome helps the brain-current evidence

The gut microbiota-brain axis has been recognized as a network of connections that provides communication between the gut microflora and both central and autonomic nervous system. The gut microbiota alteration has been targeted for therapy in various neurodegenerative and psychiatric disbalances. Psychobiotics are probiotics that contribute beneficially to the brain function and the host mental health as a result of an interaction with the commensal gut bacteria, although their mechanism of action has not been completely revealed. In this state-of-art review, the findings about the potential therapeutic effects of the psychobiotics alone or in combination with conventional medicine in the treatment of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, as well as in some psychiatric diseases like depression, schizophrenia, and bipolar disorder, have been summarized. The evidence of the psychobiotics therapeutic outcomes obtained in preclinical and clinical trials have been given respectively for the observed neurodegenerative and psychiatric disorders.     

Prognostic value of non-invasive scores based on liver stiffness measurement,spleen diameter and platelets in HIV-infected patients

Background and Aims

People living with HIV (PLWH) are at high risk for advanced chronic liver disease and related adverse outcomes. We aimed to validate the prognostic value of non-invasive scores based on liver stiffness measurement (LSM) and on markers of portal hypertension (PH), namely platelets and spleen diameter, in PLWH.

Methods

We combined data from eight international cohorts of PLWH with available non-invasive scores, including LSM and the composite biomarkers liver stiffness-spleen size-to-platelet ratio score (LSPS), LSM-to-Platelet ratio (LPR) and PH risk score. Incidence and predictors of all-cause mortality, any liver-related event and classical hepatic decompensation were determined by survival analysis, controlling for competing risks for the latter two. Non-invasive scores were assessed and compared using area under the receiver operating curve (AUROC).

Results

We included 1695 PLWH (66.8% coinfected with hepatitis C virus). During a median follow-up of 4.7 (interquartile range 2.8–7.7) years, the incidence rates of any liver-related event, all-cause mortality and hepatic decompensation were 13.7 per 1000 persons-year (PY) (95% confidence interval [CI], 11.4–16.3), 13.8 per 1000 PY (95% CI, 11.6–16.4) and 9.9 per 1000 PY (95% CI, 8.1–12.2), respectively. The AUROC of LSM was similar to that of the composite biomarkers, ranging between 0.83 and 0.86 for any liver-related event, 0.79–0.85 for all-cause mortality and 0.87–0.88 for classical hepatic decompensation. All individual non-invasive scores remained independent predictors of clinical outcomes in multivariable analysis.

Conclusions

Non-invasive scores based on LSM, spleen diameter and platelets predict clinical outcomes in PLWH. Composite biomarkers do not achieve higher prognostic performance compared to LSM alone.