International Journal of Molecular Sciences

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18 pages, 122750 KiB

Open AccessArticle

Autosomal Dominant Alzheimer’s Disease Mutations in Human Microglia Are Not Sufficient to Trigger Amyloid Pathology in WT Mice but Might Affect Pathology in 5XFAD Mice

by Carmen Romero-Molina, Sarah M. Neuner, Marcelina Ryszawiec, Alice Pébay, Dominantly Inherited Alzheimer Network, Edoardo Marcora and Alison Goate

Int. J. Mol. Sci. 2024, 25(5), 2565; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25052565 - 22 Feb 2024

Viewed by 1247

Abstract

Several genetic variants that affect microglia function have been identified as risk factors for Alzheimer’s Disease (AD), supporting the importance of this cell type in disease progression. However, the effect of autosomal dominant mutations in the amyloid precursor protein (APP) or [...] Read more.

Several genetic variants that affect microglia function have been identified as risk factors for Alzheimer’s Disease (AD), supporting the importance of this cell type in disease progression. However, the effect of autosomal dominant mutations in the amyloid precursor protein (APP) or the presenilin (PSEN1/2) genes has not been addressed in microglia in vivo. We xenotransplanted human microglia derived from non-carriers and carriers of autosomal dominant AD (ADAD)-causing mutations in the brain of hCSF1 WT or 5XFAD mice. We observed that ADAD mutations in microglia are not sufficient to trigger amyloid pathology in WT mice. In 5XFAD mice, we observed a non-statistically significant increase in amyloid plaque volume and number of dystrophic neurites, coupled with a reduction in plaque-associated microglia in the brain of mice xenotransplanted with ADAD human microglia compared to mice xenotransplanted with non-ADAD microglia. In addition, we observed a non-statistically significant impairment in working and contextual memory in 5XFAD mice xenotransplanted with ADAD microglia compared to those xenotransplanted with non-ADAD-carrier microglia. We conclude that, although not sufficient to initiate amyloid pathology in the healthy brain, mutations in APP and PSEN1 in human microglia might cause mild changes in pathological and cognitive outcomes in 5XFAD mice in a manner consistent with increased AD risk. Full article

(This article belongs to the Special Issue Neuroinflammation in the Pathogenesis of Alzheimer's Disease and Related Dementias)

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11 pages, 1660 KiB

Open AccessCommunication

Long-Term Pioglitazone Treatment Has No Significant Impact on Microglial Activation and Tau Pathology in P301S Mice

by Lea Helena Kunze, François Ruch, Gloria Biechele, Florian Eckenweber, Karin Wind-Mark, Lina Dinkel, Paul Feyen, Peter Bartenstein, Sibylle Ziegler, Lars Paeger, Sabina Tahirovic, Jochen Herms and Matthias Brendel

Int. J. Mol. Sci. 2023, 24(12), 10106; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241210106 - 14 Jun 2023

Cited by 2 | Viewed by 1147

Abstract

Neuroinflammation is one disease hallmark on the road to neurodegeneration in primary tauopathies. Thus, immunomodulation might be a suitable treatment strategy to delay or even prevent the occurrence of symptoms and thus relieve the burden for patients and caregivers. In recent years, the [...] Read more.

Neuroinflammation is one disease hallmark on the road to neurodegeneration in primary tauopathies. Thus, immunomodulation might be a suitable treatment strategy to delay or even prevent the occurrence of symptoms and thus relieve the burden for patients and caregivers. In recent years, the peroxisome proliferator-activated receptor γ (PPARγ) has received increasing attention as it is immediately involved in the regulation of the immune system and can be targeted by the anti-diabetic drug pioglitazone. Previous studies have shown significant immunomodulation in amyloid-β (Aβ) mouse models by pioglitazone. In this study, we performed long-term treatment over six months in P301S mice as a tauopathy model with either pioglitazone or placebo. We performed serial 18 kDa translocator protein positron-emission-tomography (TSPO-PET) imaging and terminal immunohistochemistry to assess microglial activation during treatment. Tau pathology was quantified via immunohistochemistry at the end of the study. Long-term pioglitazone treatment had no significant effect on TSPO-PET, immunohistochemistry read-outs of microglial activation, or tau pathology levels in P301S mice. Thus, we conclude that pioglitazone modifies the time course of Aβ-dependent microglial activation, but does not significantly modulate microglial activation in response to tau pathology. Full article

(This article belongs to the Special Issue Neuroinflammation in the Pathogenesis of Alzheimer's Disease and Related Dementias)

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26 pages, 26907 KiB

Open AccessArticle

L-Type Ca²⁺ Channel Inhibition Rescues the LPS-Induced Neuroinflammatory Response and Impairments in Spatial Memory and Dendritic Spine Formation

by Jieun Kim, Seong Gak Jeon, Ha-Ram Jeong, HyunHee Park, Jae-Ick Kim and Hyang-Sook Hoe

Int. J. Mol. Sci. 2022, 23(21), 13606; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113606 - 6 Nov 2022

Cited by 6 | Viewed by 2545

Abstract

Ca²⁺ signaling is implicated in the transition between microglial surveillance and activation. Several L-type Ca²⁺ channel blockers (CCBs) have been shown to ameliorate neuroinflammation by modulating microglial activity. In this study, we examined the effects of the L-type CCB felodipine on [...] Read more.

Ca²⁺ signaling is implicated in the transition between microglial surveillance and activation. Several L-type Ca²⁺ channel blockers (CCBs) have been shown to ameliorate neuroinflammation by modulating microglial activity. In this study, we examined the effects of the L-type CCB felodipine on LPS-mediated proinflammatory responses. We found that felodipine treatment significantly diminished LPS-evoked proinflammatory cytokine levels in BV2 microglial cells in an L-type Ca²⁺ channel-dependent manner. In addition, felodipine leads to the inhibition of TLR4/AKT/STAT3 signaling in BV2 microglial cells. We further examined the effects of felodipine on LPS-stimulated neuroinflammation in vivo and found that daily administration (3 or 7 days, i.p.) significantly reduced LPS-mediated gliosis and COX-2 and IL-1β levels in C57BL/6 (wild-type) mice. Moreover, felodipine administration significantly reduced chronic neuroinflammation-induced spatial memory impairment, dendritic spine number, and microgliosis in C57BL/6 mice. Taken together, our results suggest that the L-type CCB felodipine could be repurposed for the treatment of neuroinflammation/cognitive function-associated diseases. Full article

(This article belongs to the Special Issue Neuroinflammation in the Pathogenesis of Alzheimer's Disease and Related Dementias)

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25 pages, 3103 KiB

Open AccessArticle

Sex and APOE Genotype Alter the Basal and Induced Inflammatory States of Primary Microglia from APOE Targeted Replacement Mice

by Isha Mhatre-Winters, Aseel Eid, Yoonhee Han, Kim Tieu and Jason R. Richardson

Int. J. Mol. Sci. 2022, 23(17), 9829; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179829 - 29 Aug 2022

Cited by 6 | Viewed by 2695

Abstract

The sex and APOE4 genotype are significant risk factors for Alzheimer’s disease (AD); however, the mechanism(s) responsible for this interaction are still a matter of debate. Here, we assess the responses of mixed-sex and sex-specific APOE3 and APOE4 primary microglia (PMG) to lipopolysaccharide [...] Read more.

The sex and APOE4 genotype are significant risk factors for Alzheimer’s disease (AD); however, the mechanism(s) responsible for this interaction are still a matter of debate. Here, we assess the responses of mixed-sex and sex-specific APOE3 and APOE4 primary microglia (PMG) to lipopolysaccharide and interferon-gamma. In our investigation, inflammatory cytokine profiles were assessed by qPCR and multiplex ELISA assays. Mixed-sex APOE4 PMG exhibited higher basal mRNA expression and secreted levels of TNFa and IL1b. In sex-specific cultures, basal expression and secreted levels of IL1b, TNFa, IL6, and NOS2 were 2–3 fold higher in APOE4 female PMG compared to APOE4 males, with both higher than APOE3 cells. Following an inflammatory stimulus, the expression of pro-inflammatory cytokines and the secreted cytokine level were upregulated in the order E4 female > E4 male > E3 female > E3 male in sex-specific cultures. These data indicate that the APOE4 genotype and female sex together contribute to a greater inflammatory response in PMG isolated from targeted replacement humanized APOE mice. These data are consistent with clinical data and indicate that sex-specific PMG may provide a platform for exploring mechanisms of genotype and sex differences in AD related to neuroinflammation and neurodegeneration. Full article

(This article belongs to the Special Issue Neuroinflammation in the Pathogenesis of Alzheimer's Disease and Related Dementias)

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Review

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18 pages, 1527 KiB

Open AccessReview

Periodontitis: A Plausible Modifiable Risk Factor for Neurodegenerative Diseases? A Comprehensive Review

by Adelina S. Plachokova, Jolijn Gjaltema, Eliza R. C. Hagens, Zahra Hashemi, Tim B. A. Knüppe, Thomas J. M. Kootstra, Anita Visser and Bastiaan R. Bloem

Int. J. Mol. Sci. 2024, 25(8), 4504; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25084504 - 19 Apr 2024

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Abstract

The aim of this comprehensive review is to summarize recent literature on associations between periodontitis and neurodegenerative diseases, explore the bidirectionality and provide insights into the plausible pathogenesis. For this purpose, systematic reviews and meta-analyses from PubMed, Medline and EMBASE were considered. Out [...] Read more.

The aim of this comprehensive review is to summarize recent literature on associations between periodontitis and neurodegenerative diseases, explore the bidirectionality and provide insights into the plausible pathogenesis. For this purpose, systematic reviews and meta-analyses from PubMed, Medline and EMBASE were considered. Out of 33 retrieved papers, 6 articles complying with the inclusion criteria were selected and discussed. Additional relevant papers for bidirectionality and pathogenesis were included. Results show an association between periodontitis and Alzheimer’s disease, with odds ratios of 3 to 5. A bidirectional relationship is suspected. For Parkinson’s disease (PD), current evidence for an association appears to be weak, although poor oral health and PD seem to be correlated. A huge knowledge gap was identified. The plausible mechanistic link for the association between periodontitis and neurodegenerative diseases is the interplay between periodontal inflammation and neuroinflammation. Three pathways are hypothesized in the literature, i.e., humoral, neuronal and cellular, with a clear role of periodontal pathogens, such as Porphyromonas gingivalis. Age, gender, race, smoking, alcohol intake, nutrition, physical activity, socioeconomic status, stress, medical comorbidities and genetics were identified as common risk factors for periodontitis and neurodegenerative diseases. Future research with main emphasis on the collaboration between neurologists and dentists is encouraged. Full article

(This article belongs to the Special Issue Neuroinflammation in the Pathogenesis of Alzheimer's Disease and Related Dementias)

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21 pages, 3667 KiB

Open AccessReview

Necrosis Links Neurodegeneration and Neuroinflammation in Neurodegenerative Disease

by Hidenori Homma, Hikari Tanaka, Kyota Fujita and Hitoshi Okazawa

Int. J. Mol. Sci. 2024, 25(7), 3636; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25073636 - 24 Mar 2024

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Abstract

The mechanisms of neuronal cell death in neurodegenerative disease remain incompletely understood, although recent studies have made significant advances. Apoptosis was previously considered to be the only mechanism of neuronal cell death in neurodegenerative diseases. However, recent findings have challenged this dogma, identifying [...] Read more.

The mechanisms of neuronal cell death in neurodegenerative disease remain incompletely understood, although recent studies have made significant advances. Apoptosis was previously considered to be the only mechanism of neuronal cell death in neurodegenerative diseases. However, recent findings have challenged this dogma, identifying new subtypes of necrotic neuronal cell death. The present review provides an updated summary of necrosis subtypes and discusses their potential roles in neurodegenerative cell death. Among numerous necrosis subtypes, including necroptosis, paraptosis, ferroptosis, and pyroptosis, transcriptional repression-induced atypical cell death (TRIAD) has been identified as a potential mechanism of neuronal cell death. TRIAD is induced by functional deficiency of TEAD-YAP and self-amplifies via the release of HMGB1. TRIAD is a feasible potential mechanism of neuronal cell death in Alzheimer’s disease and other neurodegenerative diseases. In addition to induction of cell death, HMGB1 released during TRIAD activates brain inflammatory responses, which is a potential link between neurodegeneration and neuroinflammation. Full article

(This article belongs to the Special Issue Neuroinflammation in the Pathogenesis of Alzheimer's Disease and Related Dementias)

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15 pages, 929 KiB

Open AccessReview

The Influence of Kynurenine Metabolites on Neurodegenerative Pathologies

by Suhrud Pathak, Rishi Nadar, Shannon Kim, Keyi Liu, Manoj Govindarajulu, Preston Cook, Courtney S. Watts Alexander, Muralikrishnan Dhanasekaran and Timothy Moore

Int. J. Mol. Sci. 2024, 25(2), 853; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25020853 - 10 Jan 2024

Cited by 2 | Viewed by 1448

Abstract

As the kynurenine pathway’s links to inflammation, the immune system, and neurological disorders became more apparent, it attracted more and more attention. It is the main pathway through which the liver breaks down Tryptophan and the initial step in the creation of nicotinamide [...] Read more.

As the kynurenine pathway’s links to inflammation, the immune system, and neurological disorders became more apparent, it attracted more and more attention. It is the main pathway through which the liver breaks down Tryptophan and the initial step in the creation of nicotinamide adenine dinucleotide (NAD+) in mammals. Immune system activation and the buildup of potentially neurotoxic substances can result from the dysregulation or overactivation of this pathway. Therefore, it is not shocking that kynurenines have been linked to neurological conditions (Depression, Parkinson’s, Alzheimer’s, Huntington’s Disease, Schizophrenia, and cognitive deficits) in relation to inflammation. Nevertheless, preclinical research has demonstrated that kynurenines are essential components of the behavioral analogs of depression and schizophrenia-like cognitive deficits in addition to mediators associated with neurological pathologies due to their neuromodulatory qualities. Neurodegenerative diseases have been extensively associated with neuroactive metabolites of the kynurenine pathway (KP) of tryptophan breakdown. In addition to being a necessary amino acid for protein synthesis, Tryptophan is also transformed into the important neurotransmitters tryptamine and serotonin in higher eukaryotes. In this article, a summary of the KP, its function in neurodegeneration, and the approaches being used currently to target the route therapeutically are discussed. Full article

(This article belongs to the Special Issue Neuroinflammation in the Pathogenesis of Alzheimer's Disease and Related Dementias)

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16 pages, 2488 KiB

Open AccessReview

Role of cGAS–Sting Signaling in Alzheimer’s Disease

by Manoj Govindarajulu, Sindhu Ramesh, McNeil Beasley, Graham Lynn, Caleigh Wallace, Sammie Labeau, Suhrud Pathak, Rishi Nadar, Timothy Moore and Muralikrishnan Dhanasekaran

Int. J. Mol. Sci. 2023, 24(9), 8151; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24098151 - 2 May 2023

Cited by 4 | Viewed by 3463

Abstract

There is mounting evidence that the development of Alzheimer’s disease (AD) interacts extensively with immunological processes in the brain and extends beyond the neuronal compartment. Accumulation of misfolded proteins can activate an innate immune response that releases inflammatory mediators and increases the severity [...] Read more.

There is mounting evidence that the development of Alzheimer’s disease (AD) interacts extensively with immunological processes in the brain and extends beyond the neuronal compartment. Accumulation of misfolded proteins can activate an innate immune response that releases inflammatory mediators and increases the severity and course of the disease. It is widely known that type-I interferon-driven neuroinflammation in the central nervous system (CNS) accelerates the development of numerous acute and chronic CNS diseases. It is becoming better understood how the cyclic GMP–AMP synthase (cGAS) and its adaptor protein Stimulator of Interferon Genes (STING) triggers type-I IFN-mediated neuroinflammation. We discuss the principal elements of the cGAS–STING signaling pathway and the mechanisms underlying the association between cGAS–STING activity and various AD pathologies. The current understanding of beneficial and harmful cGAS–STING activity in AD and the current treatment pathways being explored will be discussed in this review. The cGAS–STING regulation offers a novel therapeutic opportunity to modulate inflammation in the CNS because it is an upstream regulator of type-I IFNs Full article

(This article belongs to the Special Issue Neuroinflammation in the Pathogenesis of Alzheimer's Disease and Related Dementias)

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29 pages, 1453 KiB

Open AccessReview

Glial Cell-Mediated Neuroinflammation in Alzheimer’s Disease

by Nour F. Al-Ghraiybah, Junwei Wang, Amer E. Alkhalifa, Andrew B. Roberts, Ruchika Raj, Euitaek Yang and Amal Kaddoumi

Int. J. Mol. Sci. 2022, 23(18), 10572; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810572 - 12 Sep 2022

Cited by 32 | Viewed by 8464

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder; it is the most common cause of dementia and has no treatment. It is characterized by two pathological hallmarks, the extracellular deposits of amyloid beta (Aβ) and the intraneuronal deposits of Neurofibrillary tangles (NFTs). Yet, [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder; it is the most common cause of dementia and has no treatment. It is characterized by two pathological hallmarks, the extracellular deposits of amyloid beta (Aβ) and the intraneuronal deposits of Neurofibrillary tangles (NFTs). Yet, those two hallmarks do not explain the full pathology seen with AD, suggesting the involvement of other mechanisms. Neuroinflammation could offer another explanation for the progression of the disease. This review provides an overview of recent advances on the role of the immune cells’ microglia and astrocytes in neuroinflammation. In AD, microglia and astrocytes become reactive by several mechanisms leading to the release of proinflammatory cytokines that cause further neuronal damage. We then provide updates on neuroinflammation diagnostic markers and investigational therapeutics currently in clinical trials to target neuroinflammation. Full article

(This article belongs to the Special Issue Neuroinflammation in the Pathogenesis of Alzheimer's Disease and Related Dementias)

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