Neuroinflammation In Alzheimer Research Articles

PET Imaging of Neuroinflammation in Alzheimer's Disease.

Neuroinflammation play an important role in Alzheimer’s disease pathogenesis. Advances in molecular imaging using positron emission tomography have provided insights into the time course of neuroinflammation and its relation with Alzheimer’s disease central pathologies in patients and in animal disease models. Recent single-cell sequencing and transcriptomics indicate dynamic disease-associated microglia and astrocyte profiles in Alzheimer’s disease. Mitochondrial 18-kDa translocator protein is the most widely investigated target for neuroinflammation imaging. New generation of translocator protein tracers with improved performance have been developed and evaluated along with tau and amyloid imaging for assessing the disease progression in Alzheimer’s disease continuum. Given that translocator protein is not exclusively expressed in glia, alternative targets are under rapid development, such as monoamine oxidase B, matrix metalloproteinases, colony-stimulating factor 1 receptor, imidazoline-2 binding sites, cyclooxygenase, cannabinoid-2 receptor, purinergic P2X7 receptor, P2Y12 receptor, the fractalkine receptor, triggering receptor expressed on myeloid cells 2, and receptor for advanced glycation end products. Promising targets should demonstrate a higher specificity for cellular locations with exclusive expression in microglia or astrocyte and activation status (pro- or anti-inflammatory) with highly specific ligand to enable in vivo brain imaging. In this review, we summarised recent advances in the development of neuroinflammation imaging tracers and provided an outlook for promising targets in the future.

Blood-Based Biomarkers of Neuroinflammation in Alzheimer's Disease: A Central Role for Periphery?

Neuroinflammation represents a central feature in the development of Alzheimer’s disease (AD). The resident innate immune cells of the brain are the principal players in neuroinflammation, and their activation leads to a defensive response aimed at promoting β-amyloid (Aβ) clearance. However, it is now widely accepted that the peripheral immune system—by virtue of a dysfunctional blood–brain barrier (BBB)—is involved in the pathogenesis and progression of AD; microglial and astrocytic activation leads to the release of chemokines able to recruit peripheral immune cells into the central nervous system (CNS); at the same time, cytokines released by peripheral cells are able to cross the BBB and act upon glial cells, modifying their phenotype. To successfully fight this neurodegenerative disorder, accurate and sensitive biomarkers are required to be used for implementing an early diagnosis, monitoring the disease progression and treatment effectiveness. Interestingly, as a result of the bidirectional communication between the brain and the periphery, the blood compartment ends up reflecting several pathological changes occurring in the AD brain and can represent an accessible source for such biomarkers. In this review, we provide an overview on some of the most promising peripheral biomarkers of neuroinflammation, discussing their pathogenic role in AD.

In silico screening of neurokinin receptor antagonists as a therapeutic strategy for neuroinflammation in Alzheimer\u2019s disease

Neuroinflammation is one of the detrimental factors leading to neurodegeneration in Alzheimer’s disease (AD) and other neurodegenerative disorders. The activation of microglial neurokinin 1 receptor (NK1R) by substance P (SP) enhances neuroinflammation which is mediated through pro-inflammatory pathways involving NFkB, ERK1/2, and P38 and thus projects the scope and importance of NK1R inhibitors. Emphasizing the inhibitory role of N Acetyl l Tryptophan (l-NAT) on NK1R, this is the first in silico screening of l-NAT mediated NK1R antagonism. In addition, FDA- approved ligands were screened for their potential NK1R antagonism. The l-NAT was docked in XP (Extra Precision) mode while FDA-approved ligands were screened in HTVS (High Throughput Virtual Screening), SP (Standard Precision), and XP mode onto NK1R (PDB:6HLO). The l-NAT and top 3 compounds FDA-approved ligands were subjected to molecular dynamics (MD) studies of 100 ns simulation time. The XP docking of l-NAT, indacaterol, modafinil and alosetron showed good docking scores. Their 100 ns MD showed brief protein–ligand interactions with an acceptable root mean square deviation. The protein–ligand contacts depicted pi-pi stacking, pi-cation, hydrogen bonds, and water bridges with the amino acids necessary for NK1R inhibition. The variable colour band intensities on the protein–ligand contact map indicated their binding strength with amino acids. The molecular mechanics/generalized born surface area (MM-GBSA) scores suggested favourable binding free energy of the complexes. Thus, our study predicted the ability of l-NAT, indacaterol, modafinil, and alosetron as capable NK1R inhibitors that can aid to curb neuroinflammation in conditions of AD which could be further ascertained in subsequent studies.Graphic

Interleukin-10 deficiency exacerbates inflammation-induced tau pathology

BackgroundThe presence of hyperphosphorylated microtubule-associated protein tau is strongly correlated with cognitive decline and neuroinflammation in Alzheimer’s disease and related tauopathies. However, the role of inflammation and anti-inflammatory interventions in tauopathies is unclear. Our goal was to determine if removing anti-inflammatory interleukin-10 (IL-10) during an acute inflammatory challenge has any effect on neuronal tau pathology.MethodsWe induce systemic inflammation in Il10-deficient (Il10−/−) versus Il10+/+ (Non-Tg) control mice using a single intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) to examine microglial activation and abnormal hyperphosphorylation of endogenous mouse tau protein. Tau phosphorylation was quantified by Western blotting and immunohistochemistry. Microglial morphology was quantified by skeleton analysis. Cytokine expression was determined by multiplex electro chemiluminescent immunoassay (MECI) from Meso Scale Discovery (MSD).ResultsOur findings show that genetic deletion of Il10 promotes enhanced neuroinflammation and tau phosphorylation. First, LPS-induced tau hyperphosphorylation was significantly increased in Il10−/− mice compared to controls. Second, LPS-treated Il10−/− mice showed signs of neurodegeneration. Third, LPS-treated Il10−/− mice showed robust IL-6 upregulation and direct treatment of primary neurons with IL-6 resulted in tau hyperphosphorylation on Ser396/Ser404 site.ConclusionsThese data support that loss of IL-10 activates microglia, enhances IL-6, and leads to hyperphosphorylation of tau on AD-relevant epitopes in response to acute systemic inflammation.

A Computational Exploration of the Molecular Network Associated to Neuroinflammation in Alzheimer's Disease.

Neuroinflammation, as defined by the presence of classically activated microglia, is thought to play a key role in numerous neurodegenerative disorders such as Alzheimer’s disease. While modulating neuroinflammation could prove beneficial against neurodegeneration, identifying its most relevant biological processes and pharmacological targets remains highly challenging. In the present study, we combined text-mining, functional enrichment and protein-level functional interaction analyses to 1) identify the proteins significantly associated to neuroinflammation in Alzheimer’s disease over the scientific literature, 2) distinguish the key proteins most likely to control the neuroinflammatory processes significantly associated to Alzheimer's disease, 3) identify their regulatory microRNAs among those dysregulated in Alzheimer's disease and 4) assess their pharmacological targetability. 94 proteins were found to be significantly associated to neuroinflammation in Alzheimer’s disease over the scientific literature and IL4, IL10 and IL13 signaling as well as TLR-mediated MyD88- and TRAF6-dependent responses were their most significantly enriched biological processes. IL10, TLR4, IL6, AKT1, CRP, IL4, CXCL8, TNF-alpha, ITGAM, CCL2 and NOS3 were identified as the most potent regulators of the functional interaction network formed by these immune processes. These key proteins were indexed to be regulated by 63 microRNAs dysregulated in Alzheimer's disease, 13 long non-coding RNAs and targetable by 55 small molecules and 8 protein-based therapeutics. In conclusion, our study identifies eleven key proteins with the highest ability to control neuroinflammatory processes significantly associated to Alzheimer’s disease, as well as pharmacological compounds with single or pleiotropic actions acting on them. As such, it may facilitate the prioritization of diagnostic and target-engagement biomarkers as well as the development of effective therapeutic strategies against neuroinflammation in Alzheimer’s disease.

Flurbiprofen sodium microparticles and soft pellets for nose-to-brain delivery: Serum and brain levels in rats after nasal insufflation

Neuroinflammation in Alzheimer’s disease (AD) revamped the role of a preventive therapeutic action of non steroidal anti-inflammatory drugs; flurbiprofen could delay AD onset, provided its access to brain is enhanced and systemic exposure limited. Nasal administration could enable direct drug access to central nervous system (CNS) via nose-to-brain transport. Here, we investigated the insufflation, deposition, dissolution, transmucosal permeation, and in vivo transport to rat brain of flurbiprofen from nasal powders combined in an active device.Flurbiprofen sodium spray-dried microparticles as such, or soft pellets obtained by agglomeration of drug microparticles with excipients, were intranasally administered to rats by the pre-metered insufflator device. Blood and brain were collected to measure flurbiprofen levels.Excipient presence in soft pellets lowered the metered drug dose to insufflate. Nevertheless, efficiency of powder delivery by the device, measured as emitted fraction, was superior with soft pellets than microparticles, due to their coarse size. Both nasal powders resulted into rapid flurbiprofen absorption. Absolute bioavailability was 33% and 58% for microparticles and pellets, respectively. Compared to intravenous flurbiprofen, the microparticles were more efficient than soft pellets at enhancing direct drug transport to CNS. Direct Transport Percentage index evidenced that more than 60% of the intranasal dose reached the brain via direct nose-to-brain transport for both powders. Moreover, remarkable drug concentrations were measured in the olfactory bulb after microparticle delivery. Bulb connection with the entorhinal cortex, from where AD initiates, makes flurbiprofen sodium administration as nasal powder worth of further investigation in an animal model of neuroinflammation.

Acute systemic inflammation exacerbates neuroinflammation in Alzheimer's disease: IL-1β drives amplified responses in primed astrocytes and neuronal network dysfunction.

Neuroinflammation contributes to Alzheimer's disease (AD) progression. Secondary inflammatory insults trigger delirium and can accelerate cognitive decline. Individual cellular contributors to this vulnerability require elucidation. Using APP/PS1 mice and AD brain, we studied secondary inflammatory insults to investigate hypersensitive responses in microglia, astrocytes, neurons, and human brain tissue. The NLRP3 inflammasome was assembled surrounding amyloid beta, and microglia were primed, facilitating exaggerated interleukin-1β(IL-1β) responses to subsequent LPS stimulation. Astrocytes were primed to produce exaggerated chemokine responses to intrahippocampal IL-1β. Systemic LPS triggered microglial IL-1β, astrocytic chemokines, IL-6, and acute cognitive dysfunction, whereas IL-1β disrupted hippocampal gamma rhythm, all selectively in APP/PS1 mice. Brains from AD patients with infection showed elevated IL-1β and IL-6 levels. Therefore, amyloid leaves the brain vulnerable to secondary inflammation at microglial, astrocytic, neuronal, and cognitive levels, and infection amplifies neuroinflammatory cytokine synthesis in humans. Exacerbation of neuroinflammation to produce deleterious outcomes like delirium and accelerated disease progression merits careful investigation in humans.

Neurological disorders associated with impaired gut microbiota

A growing field of studies is focusing on the microbiota-gut-brain axis in order to better understand the bidirectional communication pathways between gut bacteria and the CNS. The pathophysiology of neurological disorders including Alzheimer's disease and autism has been attributed to dysregulation of gut-brain axis. Fecal microbiota transplantation is the method of transferring faeces from a healthy donor into the intestine of a recipient in order to restore the recipient's weakened intestinal flora. It's been used to treat a wide range of conditions, including recurrent Clostridium difficile infection and inflammatory bowel disease. Gut-brain psychology will aid studies on subjects such as character, memory and behaviour and will contribute to the advancement of general psychology as well as will add more light in the field of neuropsychology. Lactobacillus and Bifidobacterium, for example, are essential components of the gut microbiota. Oligosaccharides, unsaturated fatty acids, dietary fibers and polyphenols are the most popular prebiotics. Traditional fermented foods including yoghurt, natto and pickles help to balance the gut bacteria. The gut microbiota is shaped by a person's diet and gut-brain function is controlled by it. Different types of microbiota have different effects on the brain and actions through the microbiota–gut–brain axis. Via the microbiota-gut-brain axis, a healthy diet leads to a healthy gut microbiota and brain and mental health. Dysbiosis of the gut microbiota has been shown to trigger depression-like behaviours in GF mice. Proinflammatory mediators such as iNOS, ROS, COX2 and NF-B are released by microglia, resulting in neuroinflammation in Alzheimer's disease. It is becoming more widely recognized as a symptom of Autism Spectrum Disorder. The establishment of gut-brain psychology is expected to have a significant impact on psychology and related disciplines.

Genes associated with amyloid-beta-induced inflammasome-mediated neuronal death identified using functional gene trap mutagenesis approach.

Alzheimer's disease is an irreversible neurodegenerative disease, which accounts for most dementia cases. Neuroinflammation is increasingly recognised for its roles in Alzheimer's disease pathogenesis which, in part, links amyloid-beta to neuronal death. Neuroinflammatory signalling can be exhibited by neurons themselves, potentially leading to widespread neuronal cell death, although neuroinflammation is commonly associated with glial cells. The presence of the inflammasomes such as nucleotide-binding leucine-rich repeat receptors protein 1 in neurons accelerates amyloid-beta -induced neuroinflammation and has been shown to trigger neuronal pyroptosis in murine Alzheimer's disease models. However, the pathways involved in amyloid-beta activation of inflammasomes have yet to be elucidated. In this study, a gene trap mutagenesis approach was utilised to resolve the genes functionally involved in inflammasome signalling within neurons, and the mechanism behind amyloid-beta-induced neuronal death. The results indicate that amyloid-beta significantly accelerated neuroinflammatory cell death in the presence of a primed inflammasome (the NLR family pyrin domain-containing 1). The mutagenesis screen discovered the atypical mitochondrial Ras homolog family member T1 as a significant contributor to amyloid-beta-induced inflammasome -mediated neuronal death. The mutagenesis screen also identified two genes involved in transforming growth factor beta signalling, namely Transforming Growth Factor Beta Receptor 1 and SNW domain containing 1. Additionally, a gene associated with cytoskeletal reorganisation, SLIT-ROBO Rho GTPase Activating Protein 3 was found to be neuroprotective. In conclusion, these genes could play important roles in inflammasome signalling in neurons, which makes them promising therapeutic targets for future drug development against neuroinflammation in Alzheimer's disease.

Inhibition of MK2 kinase as a potential therapeutic target to control neuroinflammation in Alzheimer’s disease

Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases [1,2]. The disease affects a global population of over 40 million, along with a burden of 7.7 million new cases ever...

Extracellular signal-regulated kinase regulates microglial immune responses in Alzheimer's disease.

The importance of mitogen-activated protein kinase (MAPK) pathway signaling in regulating microglia-mediated neuroinflammation in Alzheimer's disease (AD) remains unclear. We examined the role of MAPK signaling in microglia using a preclinical model of AD pathology and quantitative proteomics studies of postmortem human brains. In multiplex immunoassay analyses of MAPK phosphoproteins in acutely isolated microglia and brain tissue from 5xFAD mice, we found phosphorylated extracellular signal-regulated kinase (ERK) was the most strongly upregulated phosphoprotein within the MAPK pathway in acutely isolated microglia, but not whole-brain tissue from 5xFAD mice. The importance of ERK signaling in primary microglia cultures was next investigated using transcriptomic profiling and functional assays of amyloid-β and neuronal phagocytosis, which confirmed that ERK is a critical regulator of IFNγ-mediated pro-inflammatory activation of microglia, although it was also partly important for constitutive microglial functions. Phospho-ERK was an upstream regulator of disease-associated microglial gene expression (Trem2, Tyrobp), as well as several human AD risk genes (Bin1, Cd33, Trem2, Cnn2), indicative of the importance of microglial ERK signaling in AD pathology. Quantitative proteomic analyses of postmortem human brain showed that ERK1 and ERK2 were the only MAPK proteins with increased protein expression and positive associations with neuropathological grade. In a human brain phosphoproteomic study, we found evidence for increased flux through the ERK signaling pathway in AD. Overall, our analyses strongly suggest that ERK phosphorylation, particularly in microglia in mouse models, is a regulator of pro-inflammatory immune responses in AD pathogenesis.

Unique molecular characteristics and microglial origin of Kv1.3 channel–positive brain myeloid cells in Alzheimer’s disease

Kv1.3 potassium channels, expressed by proinflammatory central nervous system mononuclear phagocytes (CNS-MPs), are promising therapeutic targets for modulating neuroinflammation in Alzheimer's disease (AD). The molecular characteristics of Kv1.3-high CNS-MPs and their cellular origin from microglia or CNS-infiltrating monocytes are unclear. While Kv1.3 blockade reduces amyloid beta (Aβ) burden in mouse models, the downstream immune effects on molecular profiles of CNS-MPs remain unknown. We show that functional Kv1.3 channels are selectively expressed by a subset of CD11b+CD45+ CNS-MPs acutely isolated from an Aβ mouse model (5xFAD) as well as fresh postmortem human AD brain. Transcriptomic profiling of purified CD11b+Kv1.3+ CNS-MPs, CD11b+CD45int Kv1.3neg microglia, and peripheral monocytes from 5xFAD mice revealed that Kv1.3-high CNS-MPs highly express canonical microglial markers (Tmem119, P2ry12) and are distinct from peripheral Ly6chigh/Ly6clow monocytes. Unlike homeostatic microglia, Kv1.3-high CNS-MPs express relatively lower levels of homeostatic genes, higher levels of CD11c, and increased levels of glutamatergic transcripts, potentially representing phagocytic uptake of neuronal elements. Using irradiation bone marrow CD45.1/CD45.2 chimerism in 5xFAD mice, we show that Kv1.3+ CNS-MPs originate from microglia and not blood-derived monocytes. We show that Kv1.3 channels regulate membrane potential and early signaling events in microglia. Finally, in vivo blockade of Kv1.3 channels in 5xFAD mice by ShK-223 reduced Aβ burden, increased CD11c+ CNS-MPs, and expression of phagocytic genes while suppressing proinflammatory genes (IL1b). Our results confirm the microglial origin and identify unique molecular features of Kv1.3-expressing CNS-MPs. In addition, we provide evidence for CNS immunomodulation by Kv1.3 blockers in AD mouse models resulting in a prophagocytic phenotype.

Neuroinflammation in Alzheimer's disease and beneficial action of luteolin.

Alzheimer's disease (AD), already the world's most common form of dementia, is projected to continue increasing in prevalence over the next several decades. The current lack of understanding of the pathogenesis of AD has hampered the development of effective treatments. Historically, AD research has been predicated on the amyloid cascade hypothesis (ACH), which attributes disease progression to the build-up of amyloid protein. However, multiple clinical studies of drugs interfering with ACH have failed to show any benefit demonstrating that AD etiology is more complex than previously thought. Here we review the current literature on the emerging key role of neuroinflammation, especially activation of microglia, in AD pathogenesis. Moreover, we provide compelling evidence that certain flavonoids, especially luteolin formulated in olive pomace oil together with hydroxytyrosol, offers a reasonable prophylactic treatment approach due to its many beneficial actions.

Olfactory Impairment Is Related to Tau Pathology and Neuroinflammation in Alzheimer's Disease.

Olfactory impairment is evident in Alzheimer's disease (AD); however, its precise relationships with clinical biomarker measures of tau pathology and neuroinflammation are not well understood. To determine if odor identification performance measured with the University of Pennsylvania Smell Identification Test (UPSIT) is related to in vivo measures of tau pathology and neuroinflammation. Cognitively normal and cognitively impaired participants were selected from an established research cohort of adults aged 50 and older who underwent neuropsychological testing, brain MRI, and amyloid PET. Fifty-four participants were administered the UPSIT. Forty-one underwent 18F-MK-6240 PET (measuring tau pathology) and fifty-three underwent 11C-PBR28 PET (measuring TSPO, present in activated microglia). Twenty-three participants had lumbar puncture to measure CSF concentrations of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-β (Aβ42). Low UPSIT performance was associated with greater18F-MK-6240 binding in medial temporal cortex, hippocampus, middle/inferior temporal gyri, inferior parietal cortex, and posterior cingulate cortex (p < 0.05). Similar relationships were seen for 11C-PBR28. These relationships were primarily driven by amyloid-positive participants. Lower UPSIT performance was associated with greater CSF concentrations of t-tau and p-tau (p < 0.05). Amyloid status and cognitive status exhibited independent effects on UPSIT performance (p < 0.01). Olfactory identification deficits are related to extent of tau pathology and neuroinflammation, particularly in those with amyloid pathophysiology. The independent association of amyloid-positivity and cognitive impairment with odor identification suggests that low UPSIT performance may be a marker for AD pathophysiology in cognitive normal individuals, although impaired odor identification is associated with both AD and non-AD related neurodegeneration.NCT Registration Numbers: NCT03373604; NCT02831283.

Fully defined human pluripotent stem cell-derived microglia and tri-culture system model C3 production in Alzheimer's disease.

Aberrant inflammation in the central nervous system (CNS) has been implicated as a major player in the pathogenesis of human neurodegenerative disease. We developed a novel approach to derive microglia from human pluripotent stem cells (hPSCs) and built a defined hPSC-derived tri-culture system containing pure populations of hPSC-derived microglia, astrocytes, and neurons to dissect cellular crosstalk along the neuroinflammatory axis in vitro.We used the tri-culture system to model neuroinflammation in Alzheimer’s Disease with hPSCs harboring the APPSWE+/+ mutation and their isogenic control. We found that complement C3, a protein that is increased under inflammatory conditions and implicated in synaptic loss, is potentiated in tri-culture and further enhanced in APPSWE+/+ tri-cultures due to microglia initiating reciprocal signaling with astrocytes to produce excess C3. Our study defines the major cellular players contributing to increased C3 in AD and presents a broadly applicable platform to study neuroinflammation in human disease.

The role of innate immune genes in Alzheimer's disease.

Purpose of reviewThe aim of this study was to provide an update on the role of the innate immune system and neuroinflammation in the pathogenesis of Alzheimer's disease, with an emphasis on microglial receptors CD33 and TREM2.Recent findingsGenome-wide association studies (GWAS) have identified many Alzheimer's disease risk genes related to immune response and microglia including the phagocytic receptors CD33 and TREM2. Recent GWAS and pathway analyses emphasize the crucial role of the innate immune system and neuroinflammation in the pathogenesis of Alzheimer's disease. Disease-associated microglia have been characterized by TREM2-dependent upregulation of phagocytic and lipid metabolism genes. Impaired microglial phagocytosis results in amyloid beta (Aβ) accumulation leading to neuroinflammation that is the primary cause of neurodegeneration. CD33 and TREM2 modulate neuroinflammation in Alzheimer's disease and have emerged as therapeutic targets in Alzheimer's disease. Progress has been made to inhibit CD33 by gene therapy, small molecules or immunotherapy, and to increase TREM2 activity by immunotherapy. Finally, mAbs against CD33 and TREM2 have entered clinical trials and may reduce neuroinflammation in Alzheimer's disease brain.SummaryTargeting neuroinflammation via CD33 inhibition and/or TREM2 activation may have important implications for neurodegeneration in Alzheimer's disease and may be an addition to monoclonal anti-Aβ antibody treatments that remove plaques without reducing neuroinflammation.

A Novel Treatment Strategy by Natural Products in NLRP3 Inflammasome-Mediated Neuroinflammation in Alzheimer's and Parkinson's Disease.

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative diseases. Many studies have demonstrated that the release of NLRP3 inflammasome-mediated proinflammatory cytokines by the excessive activation of microglia is associated with the pathogenesis of AD and PD and suggested that the NLRP3 inflammasome plays an important role in AD and PD development. In both diseases, various stimuli, such as Aβ and α-synuclein, accelerate the formation of the NLRP3 inflammasome in microglia and induce pyroptosis through the expression of interleukin (IL)-1β, caspase-1, etc., where neuroinflammation contributes to gradual progression and deterioration. However, despite intensive research, the exact function and regulation of the NLRP3 inflammasome has not yet been clearly identified. Moreover, there have not yet been any experiments of clinical use, although many studies have recently been conducted to improve treatment of inflammatory diseases using various inhibitors for NLRP3 inflammasome pathways. However, recent studies have reported that various natural products show improvement effects in the in vivo models of AD and PD through the regulation of NLRP3 inflammasome assembly. Therefore, the present review provides an overview of natural extraction studies aimed at the prevention or treatment of NLRP3 inflammasome-mediated neurological disorders. It is suggested that the discovery and development of these various natural products could be a potential strategy for NLRP3 inflammasome-mediated AD and PD treatment.

Possible Preventive Effect of Donepezil and Hyoscyamoside by Reduction of Plaque Formation and Neuroinflammation in Alzheimer's Disease.

Background:Alzheimer disease (AD) is the most common age-dependent dementia. The complex natural accumulation of amyloid beta (Aβ) precursor protein in hippocampus neurons is regarded as the earliest pathological feature of AD, although there are cholinergic assumptions and effective inflammation in AD. In this animal experimental study, we evaluated the preventive effect of hyoscyamoside (Hyo) and donepezil (Dz) on plaque formation and improvement of neurogenic inflammation in AD rats.Methods:Dz was prepared and Hyo (steroidal saponin) was isolated from Hyoscymus niger. Then, Wistar rats divided into five groups including negative and positive controls, AD, Dz, and Hyo treatment groups based on the drug exposure and their behavioral alternation was examined using Morris water maze (MWM) test. Bielschowsky staining was used to detect the nerve fibers. Serum levels of interleukin (IL)-4 and IL-6 were evaluated by ELISA. The RNA expression of cyclin-dependent kinase CDK11-P58 in peripheral blood lymphocytes was performed using quantitative PCR.Results:The MWM test showed significant changes in time the models spent to find the hidden platform. The Hyo treatment group showed a notable speed change (P < 0.01). The histopathological analysis of the hippocampal tissue revealed the inhibition of Aβ formation in the treatment groups. The treatment groups had a significant decline in the serum level of IL-6, and the IL-4 serum level was increased in the Hyo and Dz treated groups. The expression levels of CDK11-P58 was significantly decreased in the treatment groups.Conclusions:In sum, the therapeutic effects of Hyo is comparable with that of Dz in AD rats by suppressing neuroinflammation. Thus, these compounds could be considered as a preventive agent in the AD therapy.

Gamma subunit of complement component 8 is a neuroinflammation inhibitor.

The complement system is part of the innate immune system that comprises several small proteins activated by sequential cleavages. The majority of these complement components, such as components 3a (C3a) and C5a, are chemotactic and pro-inflammatory. However, in this study, we revealed an inhibitory role of complement component 8 gamma (C8G) in neuroinflammation. In patients with Alzheimer's disease, who exhibit strong neuroinflammation, we found higher C8G levels in brain tissue, CSF, and plasma. Our novel findings also showed that the expression level of C8G increases in the inflamed mouse brain, and that C8G is mainly localized to brain astrocytes. Experiments using recombinant C8G protein and shRNA-mediated knockdown showed that C8G inhibits glial hyperactivation, neuroinflammation, and cognitive decline in acute and chronic animal models of Alzheimer's disease. Additionally, we identified sphingosine-1-phosphate receptor 2 (S1PR2) as a novel interaction protein of C8G and demonstrated that astrocyte-derived C8G interacts with S1PR2 to antagonize the pro-inflammatory action of S1P in microglia. Taken together, our results reveal the previously unrecognized role of C8G as a neuroinflammation inhibitor. Our findings pave the way towards therapeutic containment of neuroinflammation in Alzheimer's disease and related neurological diseases.

IPSC-Derived Microglia for Modeling Human-Specific DAMP and PAMP Responses in the Context of Alzheimer's Disease.

Neuroinflammation in Alzheimer’s disease (AD) has been the focus for identifying targetable pathways for drug development. The role of amyloid beta (Aβ), a prototype of damage-associated molecular patterns (DAMPs), has been implicated in triggering an inflammatory response. As alpha7 nicotinic acetylcholine receptor (α7 nAChR) binds Aβ with high affinity, α7 nAChR may play a role in Aβ-induced neuroinflammation. The conundrum of how α7 nAChR as the mediator of the cholinergic anti-inflammatory response may trigger an inflammatory response has not been resolved. CHRFAM7A, the uniquely human fusion gene between ULK4 and CHRNA7, is a negative regulator of α7 nAChR ionotropic function. To provide the human context, isogenic induced pluripotent stem cell (iPSC) lines were developed from CHRFAM7A null and carrier individuals by genome-editing the null line using TALENs to knock-in CHRFAM7A. In iPSC-derived microglia-like cells, CHRFAM7A mitigated Aβ uptake through the α7 nAChR. Despite the lower Aβ uptake, the presence of CHRFAM7A was associated with an innate immune response that was characterized by NF-κB activation and NF-κB target transcription (TNFA, IL6, and IL1B). LPS, a prototype PAMP, induced a heightened immune response in CHRFAM7A carriers. CHRFAM7A modified the dynamics of NF-κB translocation by prolonging its nuclear presence. CHRFAM7A modified the α7 nAChR metabotropic function, resulting in a human-specific innate immune response. This iPSC model provided an opportunity to elucidate the mechanism and establish high throughput screens.