Brain resident microglia in Alzheimer's disease: foe or friends.

The neurobiology of Alzheimer's disease (AD) is unclear due to its multifactorial nature. Although a wide range of studies revealed several pathomechanisms of AD, dementia is yet unmanageable with current pharmacotherapies. The recent growing literature illustrates the role of microglia-mediated neuroinflammation in the pathogenesis of AD. Indeed, microglia serve as predominant sentinels of the brain, which diligently monitor the neuroimmune axis by phagocytosis and releasing soluble factors. In the case of AD, microglial cells are involved in synaptic pruning and remodeling by producing inflammatory mediators. The conditional inter-transformation of classical activation (proinflammatory) or alternative activation (anti-inflammatory) microglia is responsible for most brain disorders. In this review, we discussed the role of microglia in neuroinflammatory processes in AD following the accumulation of amyloid-ß and tau proteins. We also described the prominent phenotypes of microglia, such as disease-associated microglia (DAM), dark microglia, interferon-responsive microglia (IRMs), human AD microglia (HAMs), and microglial neurodegenerative phenotype (MGnD), which are closely associated with AD incidence. Considering the key role of microglia in AD progression, microglial-based therapeutics may hold promise in mitigating cognitive deficits by addressing the neuroinflammatory responses.

SCFAs Supplementation Rescues Anxiety- and Depression-like Phenotypes Generated by Fecal Engraftment of Treatment-Resistant Depression Rats.

Alteration of gut microbiota and microbial metabolites such as short-chain fatty acids (SCFAs) coexisted with stress-generated brain disorders, including depression. Herein, we investigated the effect of SCFAs in a treatment-resistant depression (TRD) model of rat. Rats were exposed to chronic-unpredictable mild stress (CUMS) and repeated adrenocorticotropic hormone (ACTH) injections to generate a TRD-like phenotype. The cecal contents of these animals were engrafted into healthy-recipient rats and allowed to colonize for 4 weeks (TRD-FMT group). Blood, brain, colon, fecal, and cecal samples were collected for molecular studies. Rats exposed to CUMS + ACTH showed TRD-like phenotypes in sucrose-preference (SPT), forced swim (FST), and elevated plus maze (EPM) tests. The TRD-FMT group also exhibited anxiety- and depression-like behaviors. Administration of SCFAs (acetate, propionate, and butyrate at 67.5, 25, and 40 mM, respectively) for 7 days exerted robust antidepressant and antianxiety effects by restoring the levels of SCFAs in plasma and fecal samples, and proinflammatory cytokines (TNF-α and IL-6), serotonin, GABA, norepinephrine, and dopamine in the hippocampus and/or frontal cortex of TRD and TRD-FMT animals. SCFAs treatment elevated the expression of free-fatty acid receptors 2/3, BDNF, doublecortin, and zonula-occludens, and reduced the elevated plasma levels of kynurenine and quinolinic acid and increased mucus-producing goblet cells in TRD and TRD-FMT animals. In 16S sequencing results, decreased microbial diversity in TRD rats corresponds with differences in the genus of Faecalibacterium, Anaerostipes, Allobaculum, Blautia, Peptococcus, Rombustia, Ruminococcaceae_UCG-014, Ruminococcaceae_UCG-002, Solobacterium, Subdolibacterium, and Eubacterium ventriosum. SCFAs may impart beneficial effects via modulation of tryptophan metabolism, inflammation, neurotransmitters, and microbiota-gut-brain axis in TRD rats.