Ad-derived bone marrow transplant induces proinflammatory immune peripheral mechanisms accompanied by decreased neuroplasticity and reduced gut microbiome diversity affecting AD-like phenotype in the absence of Aß neuropathology.

Immune system dysfunction is increasingly recognized as a significant feature that contributes to Alzheimer's disease (AD) pathogenesis, reflected by alterations in central and peripheral responses leading to detrimental mechanisms that can contribute to the worsening of the disease. The damaging alterations in the peripheral immune system may disrupt the peripheral-central immune crosstalk, implicating the gut microbiota in this complex interaction. The central hypothesis posits that the immune signature inherently harbored in bone marrow (BM) cells can be transferred through allogeneic transplantation, influencing the recipient's immune system and modulating peripheral, gut, and brain immune responses. Employing a genetically modified mouse model to develop AD-type pathology we found that recipient wild-type (WT) mice engrafted with AD-derived BM, recapitulated the peripheral immune inflammatory donor phenotype, associated with a significant acceleration of cognitive deterioration in the absence of any overt change in AD-type amyloid neuropathology. Moreover, transcriptomic and phylogenetic 16S microbiome analysis evidence on these animals revealed a significantly impaired expression of genes associated with synaptic plasticity and neurotransmission in the brain and reduced bacteria diversity, respectively, compared to mice engrafted with WT BM. This investigation sheds light on the pivotal role of the peripheral immune system in the brain-gut-periphery axis and its profound potential to shape the trajectory of AD. In summary, this study advances our understanding of the complex interplay among the peripheral immune system, brain functionality, and the gut microbiome, which collectively influence AD onset and progression.

Transient anxiety-and depression-like behaviors are linked to the depletion of Foxp3-expressing cells via inflammasome in the brain.

Forkhead box P3 (Foxp3) is a transcription factor that influences functioning of regulatory T cells (Tregs) that modulate peripheral immune response. Treg-mediated innate immunity and Treg-mediated adaptive immunity are receiving considerable attention for their implication in mechanisms associated with anxiety and depression. Here, we demonstrated that depletion of Foxp3-expressing cells causally promotes transient anxiety- and depression-like behaviors associated with inflammasome activation in "depletion of regulatory T cell" (DEREG) mice. We found that restoration of Foxp3-expressing cells causally reverses neurobehavioral changes through alteration of innate immune responses as assessed by caspase-1 activity and interleukin-1ß (IL-1ß) release in the hippocampal formation of DEREG mice. Moreover, we found that depletion of Foxp3-expressing cells induces a significant elevation of granulocytes, monocytes, and macrophages in the blood, which are associated with transient expression of the matrix metalloprotease-9. Similarly, we found that depletion of Foxp3-expressing cells in 5xFAD, a mouse model of Alzheimer's disease (AD), exhibits elevated activated caspase-1 and promotion of IL-1ß secretion and increased the level of amyloid-beta (Aß)1-42 and Aß plaque burden in the hippocampal formation that coincided with an acceleration of cognitive decline at a presymptomatic age in the 5xFAD mice. Thus, our study provides evidence supporting the idea that Foxp3 may have a causal influence on peripheral immune responses. This, in turn, can promote an innate immune response within the brain, potentially leading to anxiety- and depression-like behaviors or cognitive decline.

Inflammasome-Mediated Neuronal-Microglial Crosstalk: a Therapeutic Substrate for the Familial C9orf72 Variant of Frontotemporal Dementia/Amyotrophic Lateral Sclerosis.

Intronic G4C2 hexanucleotide repeat expansions (HRE) of C9orf72 are the most common cause of familial variants of frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). G4C2 HREs in C9orf72 undergo non-canonical repeat-associated translation, producing dipeptide repeat (DPR) proteins, with various deleterious impacts on cellular homeostasis. While five different DPRs are produced, poly(glycine-arginine) (GR) is amongst the most toxic and is the only DPR to accumulate in the associated clinically relevant anatomical locations of the brain. Previous work has demonstrated the profound effects of a poly (GR) model of C9orf72 FTD/ALS, including motor impairment, memory deficits, neurodegeneration, and neuroinflammation. Neuroinflammation is hypothesized to be a driving factor in the disease course; microglia activation is present prior to symptom onset and persists throughout the disease. Here, using an established mouse model of C9orf72 FTD/ALS, we investigate the contributions of the nod-like receptor pyrin-containing 3 (NLRP3) inflammasome in the pathogenesis of FTD/ALS. We find that inflammasome-mediated neuroinflammation is increased with microglial activation, cleavage of caspase-1, production of IL-1ß, and upregulation of Cxcl10 in the brain of C9orf72 FTD/ALS mice. Excitingly, we find that genetic ablation of Nlrp3 significantly improved survival, protected behavioral deficits, and prevented neurodegeneration suggesting a novel mechanism involving HRE-mediated induction of innate immunity. The findings provide experimental evidence of the integral role of HRE in inflammasome-mediated innate immunity in the C9orf72 variant of FTD/ALS pathogenesis and suggest the NLRP3 inflammasome as a therapeutic target.

Exposure to World Trade Center Dust Exacerbates Cognitive Impairment and Evokes a Central and Peripheral Pro-Inflammatory Transcriptional Profile in an Animal Model of Alzheimer's Disease.

BACKGROUND: The terrorist attacks on September 11, 2001, on the World Trade Center (WTC) led to intense fires and a massive dense cloud of toxic gases and suspended pulverized debris. In the subsequent years, following the attack and cleanup efforts, a cluster of chronic health conditions emerged among First Responders (FR) who were at Ground Zero for prolonged periods and were repeatedly exposed to high levels of WTC particulate matter (WTCPM). Among those are neurological complications which may increase the risk for the development of Alzheimer's disease (AD) later in life. OBJECTIVE: We hypothesize that WTCPM dust exposure affects the immune cross-talking between the periphery and central nervous systems that may induce brain permeability ultimately promoting AD-type phenotype. METHODS: 5XFAD and wild-type mice were intranasally administered with WTCPM dust collected at Ground Zero within 72 h after the attacks. Y-maze assay and novel object recognition behavioral tests were performed for working memory deficits and learning and recognition memory, respectively. Transcriptomic analysis in the blood and hippocampus was performed and confirmed by RT qPCR. RESULTS: Mice exposed to WTCPM dust exhibited a significant impairment in spatial and recognition short and long-term memory. Furthermore, the transcriptomic analysis in the hippocampal formation and blood revealed significant changes in genes related to immune-inflammatory responses, and blood-brain barrier disruption. CONCLUSION: These studies suggest a putative peripheral-brain immune inflammatory cross-talking that may potentiate cognitive decline, identifying for the first time key steps which may be therapeutically targetable in future studies in WTC FR.

Role of Polyphenol-Derived Phenolic Acid in Mitigation of Inflammasome-Mediated Anxiety and Depression.

Overexposure to mental stress throughout life is a significant risk factor for the development of neuropsychiatric disorders, including depression and anxiety. The immune system can initiate a physiological response, releasing stress hormones and pro-inflammatory cytokines, in response to stressors. These effects can overcome allostatic physiological mechanisms and generate a pro-inflammatory environment with deleterious effects if occurring chronically. Previous studies in our lab have identified key anti-inflammatory properties of a bioavailable polyphenolic preparation BDPP and its ability to mitigate stress responses via the attenuation of NLRP3 inflammasome-dependent responses. Inflammasome activation is part of the first line of defense against stimuli of different natures, provides a rapid response, and, therefore, is of capital importance within the innate immunity response. malvidin-3-O-glucoside (MG), a natural anthocyanin present in high proportions in grapes, has been reported to exhibit anti-inflammatory effects, but its mechanisms remain poorly understood. This study aims to elucidate the therapeutic potential of MG on inflammasome-induced inflammation in vitro and in a mouse model of chronic unpredictable stress (CUS). Here, it is shown that MG is an anti-pyroptotic phenolic metabolite that targets NLRP3, NLRC4, and AIM2 inflammasomes, subsequently reducing caspase-1 and IL-1ß protein levels in murine primary cortical microglia and the brain, as its beneficial effect to counteract anxiety and depression is also demonstrated. The present study supports the role of MG to mitigate bacterial-mediated inflammation (lipopolysaccharide or LPS) in vitro and CUS-induced behavior impairment in vivo to address stress-induced inflammasome-mediated innate response.

Effect of topical administration of the microneurotrophin BNN27 in the diabetic rat retina.

PURPOSE: Diabetic retinopathy (DR) is a complex eye disease associated with diabetes mellitus. It is characterized by three pathophysiological components, namely microangiopathy, neurodegeneration, and inflammation. We recently reported that intraperitoneal administration of BNN27, a novel neurosteroidal microneurotrophin, reversed the diabetes-induced neurodegeneration and inflammation in rats treated with streptozotocin (STZ), by activating the NGF TrkA and p75 receptors. The aim of the present study was to investigate the efficacy of BNN27 to protect retinal neurons when applied topically as eye drops in the same model. METHODS: The STZ rat model of DR was employed. BNN27 was administered as eye drops to diabetic Sprague-Dawley rats for 7 days, 4 weeks post-STZ (70 mg/kg) injection. Immunohistochemistry and western blot analyses were employed to examine the viability of retinal neurons in control, diabetic, and diabetic-treated animals and the involvement of the TrkA receptor and its downstream signaling ERK1/2 kinases, respectively. RESULTS: BNN27 reversed the STZ-induced attenuation of the immunoreactive brain nitric oxide synthetase (bNOS)- and tyrosine hydroxylase (TH)-expressing amacrine cells and neurofilament (NFL)-expressing ganglion cell axons in a dose-dependent manner. In addition, BNN27 activated/phosphorylated the TrkA receptor and its downstream prosurvival signaling pathway, ERK1/2 kinases. CONCLUSIONS: The results of this study provide solid evidence regarding the efficacy of BNN27 as a neuroprotectant to the diabetic retina when administered topically, and suggest that its pharmacodynamic and pharmacokinetic profiles render it a putative therapeutic for diabetic retinopathy.

The Synthetic Microneurotrophin BNN27 Affects Retinal Function in Rats With Streptozotocin-Induced Diabetes.

BNN27, a C17-spiroepoxy derivative of DHEA, was shown to have antiapoptotic properties via mechanisms involving the nerve growth factor receptors (tropomyosin-related kinase A [TrkA]/neurotrophin receptor p75 [p75NTR]). In this study, we examined the effects of BNN27 on neural/glial cell function, apoptosis, and inflammation in the experimental rat streptozotocin (STZ) model of diabetic retinopathy (DR). The ability of BNN27 to activate the TrkA receptor and regulate p75NTR expression was investigated. BNN27 (2,10, and 50 mg/kg i.p. for 7 days) administration 4 weeks post-STZ injection (paradigm A) reversed the diabetes-induced glial activation and loss of function of amacrine cells (brain nitric oxide synthetase/tyrosine hydroxylase expression) and ganglion cell axons via a TrkA receptor (TrkAR)-dependent mechanism. BNN27 activated/phosphorylated the TrkAY490 residue in the absence but not the presence of TrkAR inhibitor and abolished the diabetes-induced increase in p75NTR expression. However, it had no effect on retinal cell death (TUNEL+ cells). A similar result was observed when BNN27 (10 mg/kg i.p.) was administered at the onset of diabetes, every other day for 4 weeks (paradigm B). However, BNN27 decreased the activation of caspase-3 in both paradigms. Finally, BNN27 reduced the proinflammatory (TNFα and IL-1ß) and increased the anti-inflammatory (IL-10 and IL-4) cytokine levels. These findings suggest that BNN27 has the pharmacological profile of a therapeutic for DR, since it targets both the neurodegenerative and inflammatory components of the disease.

Melatonin ameliorates low-grade inflammation and oxidative stress in young Zucker diabetic fatty rats.

The aim of this study was to investigate the effects of melatonin on low-grade inflammation and oxidative stress in young male Zucker diabetic fatty (ZDF) rats, an experimental model of metabolic syndrome and type 2 diabetes mellitus (T2DM). ZDF rats (n = 30) and lean littermates (ZL) (n = 30) were used. At 6 wk of age, both lean and fatty animals were subdivided into three groups, each composed of 10 rats: naive (N), vehicle treated (V), and melatonin treated (M) (10 mg/kg/day) for 6 wk. Vehicle and melatonin were added to the drinking water. Pro-inflammatory state was evaluated by plasma levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP). Also, oxidative stress was assessed by plasma lipid peroxidation (LPO), both basal and after Fe(2+)/H2O2 inducement. ZDF rats exhibited higher levels of IL-6 (112.4 ± 1.5 pg/mL), TNF-α (11.0 ± 0.1 pg/mL) and CRP (828 ± 16.0 µg/mL) compared with lean rats (IL-6, 89.9 ± 1.0, P < 0.01; TNF-α, 9.7 ± 0.4, P < 0.01; CRP, 508 ± 21.5, P < 0.001). Melatonin lowered IL-6 (10%, P < 0.05), TNF-α (10%, P < 0.05), and CRP (21%, P < 0.01). Basal and Fe(2+)/H2O2-induced LPO, expressed as malondialdehyde equivalents (µmol/L), were higher in ZDF rats (basal, 3.2 ± 0.1 versus 2.5 ± 0.1 in ZL, P < 0.01; Fe(2+)/H2O2-induced, 8.7 ± 0.2 versus 5.5 ± 0.3 in ZL; P < 0.001). Melatonin improved basal LPO (15%, P < 0.05) in ZDF rats, and Fe(2+)/H2O2- induced LPO in both ZL (15.2%, P < 0.01) and ZDF rats (39%, P < 0.001). These results demonstrated that oral melatonin administration ameliorates the pro-inflammatory state and oxidative stress, which underlie the development of insulin resistance and their consequences, metabolic syndrome, diabetes, and cardiovascular disease.