scholarly journals Microbial pathogens induce neurodegeneration in Alzheimer’s disease mice: protection by microglial regulation

2022 ◽  
Vol 19 (1) ◽  
Author(s):  
Tal Ganz ◽  
Nina Fainstein ◽  
Amit Elad ◽  
Marva Lachish ◽  
Smadar Goldfarb ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cortical Neuron ◽  
Neuronal Death ◽  
Neuronal Loss ◽  
Microbial Pathogens ◽  
Wild Type ◽  
Tlr Agonists ◽  
Neurodegenerative Process ◽  
5Xfad Mice

Abstract Background Neurodegeneration is considered the consequence of misfolded proteins’ deposition. Little is known about external environmental effects on the neurodegenerative process. Infectious agent-derived pathogen-associated molecular patterns (PAMPs) activate microglia, key players in neurodegenerative diseases. We hypothesized that systemic microbial pathogens may accelerate neurodegeneration in Alzheimer’s disease (AD) and that microglia play a central role in this process. Methods We examined the effect of an infectious environment and of microbial Toll-like receptor (TLR) agonists on cortical neuronal loss and on microglial phenotype in wild type versus 5xFAD transgenic mice, carrying mutated genes associated with familial AD. Results We examined the effect of a naturally bred environment on the neurodegenerative process. Earlier and accelerated cortical neuron loss occurred in 5xFAD mice housed in a natural (“dirty”) environment than in a specific-pathogen-free (SPF) environment, without increasing the burden of Amyloid deposits and microgliosis. Neuronal loss occurred in a microglia-rich cortical region but not in microglia-poor CA regions of the hippocampus. Environmental exposure had no effect on cortical neuron density in wild-type mice. To model the neurodegenerative process caused by the natural infectious environment, we injected systemically the bacterial endotoxin lipopolysaccharide (LPS), a TLR4 agonist PAMP. LPS caused cortical neuronal death in 5xFAD, but not wt mice. We used the selective retinoic acid receptor α agonist Am580 to regulate microglial activation. In primary microglia isolated from 5xFAD mice, Am580 markedly attenuated TLR agonists-induced iNOS expression, without canceling their basic immune response. Intracerebroventricular delivery of Am580 in 5xFAD mice reduced significantly the fraction of (neurotoxic) iNOS + microglia and increased the fraction of (neuroprotective) TREM2 + microglia. Furthermore, intracerebroventricular delivery of Am580 prevented neurodegeneration induced by microbial TLR agonists. Conclusions Exposure to systemic infections causes neurodegeneration in brain regions displaying amyloid pathology and high local microglia density. AD brains exhibit increased susceptibility to microbial PAMPs’ neurotoxicity, which accelerates neuronal death. Microglial modulation protects the brain from microbial TLR agonist PAMP-induced neurodegeneration.

scholarly journals Pharmacological ablation of astrocytes reduces Aβ degradation and synaptic connectivity in an ex vivo model of Alzheimer’s disease

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Nicola Davis ◽  
Bibiana C. Mota ◽  
Larissa Stead ◽  
Emily O. C. Palmer ◽  
Laura Lombardero ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Culture Media ◽  
Ex Vivo ◽  
Wild Type ◽  
Insulin Degrading Enzyme ◽  
Ex Vivo Model ◽  
Model Of Alzheimer’S Disease ◽  
Aβ Clearance ◽  
5Xfad Mice

Abstract Background Astrocytes provide a vital support to neurons in normal and pathological conditions. In Alzheimer’s disease (AD) brains, reactive astrocytes have been found surrounding amyloid plaques, forming an astrocytic scar. However, their role and potential mechanisms whereby they affect neuroinflammation, amyloid pathology, and synaptic density in AD remain unclear. Methods To explore the role of astrocytes on Aβ pathology and neuroinflammatory markers, we pharmacologically ablated them in organotypic brain culture slices (OBCSs) from 5XFAD mouse model of AD and wild-type (WT) littermates with the selective astrocytic toxin L-alpha-aminoadipate (L-AAA). To examine the effects on synaptic circuitry, we measured dendritic spine number and size in OBCSs from Thy-1-GFP transgenic mice incubated with synthetic Aβ42 or double transgenics Thy-1-GFP/5XFAD mice treated with LAAA or vehicle for 24 h. Results Treatment of OBCSs with L-AAA resulted in an increased expression of pro-inflammatory cytokine IL-6 in conditioned media of WTs and 5XFAD slices, associated with changes in microglia morphology but not in density. The profile of inflammatory markers following astrocytic loss was different in WT and transgenic cultures, showing reductions in inflammatory mediators produced in astrocytes only in WT sections. In addition, pharmacological ablation of astrocytes led to an increase in Aβ levels in homogenates of OBCS from 5XFAD mice compared with vehicle controls, with reduced enzymatic degradation of Aβ due to lower neprilysin and insulin-degrading enzyme (IDE) expression. Furthermore, OBSCs from wild-type mice treated with L-AAA and synthetic amyloid presented 56% higher levels of Aβ in culture media compared to sections treated with Aβ alone, concomitant with reduced expression of IDE in culture medium, suggesting that astrocytes contribute to Aβ clearance and degradation. Quantification of hippocampal dendritic spines revealed a reduction in their density following L-AAA treatment in all groups analyzed. In addition, pharmacological ablation of astrocytes resulted in a decrease in spine size in 5XFAD OBCSs but not in OBCSs from WT treated with synthetic Aβ compared to vehicle control. Conclusions Astrocytes play a protective role in AD by aiding Aβ clearance and supporting synaptic plasticity.

scholarly journals Ceramide and Related-Sphingolipid Levels Are Not Altered in Disease-Associated Brain Regions of APPSLand APPSL/PS1M146LMouse Models of Alzheimer's Disease: Relationship with the Lack of Neurodegeneration?

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Laurence Barrier ◽  
Bernard Fauconneau ◽  
Anastasia Noël ◽  
Sabrina Ingrand
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Neuronal Death ◽  
Time Course ◽  
Neuronal Loss ◽  
Brain Regions ◽  
App Processing ◽  
Ceramide Accumulation ◽  
The Brain

There is evidence linking sphingolipid abnormalities, APP processing, and neuronal death in Alzheimer's disease (AD). We previously reported a strong elevation of ceramide levels in the brain of the APPSL/PS1Ki mouse model of AD, preceding the neuronal death. To extend these findings, we analyzed ceramide and related-sphingolipid contents in brain from two other mouse models (i.e., APPSLand APPSL/PS1M146L) in which the time-course of pathology is closer to that seen in most currently available models. Conversely to our previous work, ceramides did not accumulate in disease-associated brain regions (cortex and hippocampus) from both models. However, the APPSL/PS1Ki model is unique for its drastic neuronal loss coinciding with strong accumulation of neurotoxic Aβisoforms, not observed in other animal models of AD. Since there are neither neuronal loss nor toxic Aβspecies accumulation in APPSLmice, we hypothesized that it might explain the lack of ceramide accumulation, at least in this model.

scholarly journals Astrocyte remodeling in the beneficial effects of long-term voluntary exercise in Alzheimer’s disease

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Irina Belaya ◽  
Mariia Ivanova ◽  
Annika Sorvari ◽  
Marina Ilicic ◽  
Sanna Loppi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Physical Exercise ◽  
Neuronal Loss ◽  
Voluntary Exercise ◽  
Glial Fibrillary Acid Protein ◽  
Free Access ◽  
Beneficial Effects ◽  
5Xfad Mice

Abstract Background Increased physical exercise improves cognitive function and reduces pathology associated with Alzheimer’s disease (AD). However, the mechanisms underlying the beneficial effects of exercise in AD on the level of specific brain cell types remain poorly investigated. The involvement of astrocytes in AD pathology is widely described, but their exact role in exercise-mediated neuroprotection warrant further investigation. Here, we investigated the effect of long-term voluntary physical exercise on the modulation of the astrocyte state. Methods Male 5xFAD mice and their wild-type littermates had free access to a running wheel from 1.5 to 7 months of age. A battery of behavioral tests was used to assess the effects of voluntary exercise on cognition and learning. Neuronal loss, impairment in neurogenesis, beta-amyloid (Aβ) deposition, and inflammation were evaluated using a variety of histological and biochemical measurements. Sophisticated morphological analyses were performed to delineate the specific involvement of astrocytes in exercise-induced neuroprotection in the 5xFAD mice. Results Long-term voluntary physical exercise reversed cognitive impairment in 7-month-old 5xFAD mice without affecting neurogenesis, neuronal loss, Aβ plaque deposition, or microglia activation. Exercise increased glial fibrillary acid protein (GFAP) immunoreactivity and the number of GFAP-positive astrocytes in 5xFAD hippocampi. GFAP-positive astrocytes in hippocampi of the exercised 5xFAD mice displayed increases in the numbers of primary branches and in the soma area. In general, astrocytes distant from Aβ plaques were smaller in size and possessed simplified processes in comparison to plaque-associated GFAP-positive astrocytes. Morphological alterations of GFAP-positive astrocytes occurred concomitantly with increased astrocytic brain-derived neurotrophic factor (BDNF) and restoration of postsynaptic protein PSD-95. Conclusions Voluntary physical exercise modulates the reactive astrocyte state, which could be linked via astrocytic BDNF and PSD-95 to improved cognition in 5xFAD hippocampi. The molecular pathways involved in this modulation could potentially be targeted for benefit against AD.

scholarly journals GPCR19 regulates P2X7R-mediated NLRP3 inflammasomal activation of microglia by Amyloid β in Alzheimer’s diseases

2020 ◽  
Author(s):  
Jahirul Islam ◽  
Jung-Ah Cho ◽  
Ju-yong Kim ◽  
Kyung-Sun Park ◽  
Young-Jae koh ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nlrp3 Inflammasome ◽  
Memory Function ◽  
Scavenger Receptor ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Priming Phase ◽  
5Xfad Mice ◽  
The Brain

Abstract Amyloid β (Aβ) and/or ATP activates NLRP3 inflammasome (N3I) by P2 × 7R ion channel of microglia, which is crucial in neuroinflammation shown in Alzheimer’s disease (AD). Due to polymorphisms, subtypes, and ubiquitous expression of P2 × 7R, inhibition of P2 × 7R has not been effective for AD. We first report that GPCR19 is a prerequisite for P2 × 7R-mediated N3I activation and Taurodeoxycholate (TDCA), a GPCR19 ligand, inhibited the priming phase of N3I activation, suppressed P2 × 7R expression and P2 × 7R-mediated Ca++ mobilization, and N3I oligomerization which is essential for production of IL-1β/IL-18. Further, TDCA increased expression of scavenger receptor (SR) A, enhanced phagocytosis of Aβ, and decreased Aβ plaque numbers in the brain of 5x Familial Alzheimer’s disease (5xFAD) mice. TDCA also reduced microgliosis, prevented neuronal loss, and improved memory function of 5xFAD mice. The pleiotropic roles of GPCR19 in P2 × 7-mediated N3I activation suggest that targeting GPCR19 might resolve neuroinflammation in AD patients.

scholarly journals Molecular Differences and Similarities between Alzheimer's Disease and the 5XFAD Transgenic Mouse Model of Amyloidosis

2013 ◽  
Vol 6 ◽  
pp. BCI.S13025 ◽  
Author(s):  
Chera L. Maarouf ◽  
Tyler A. Kokjohn ◽  
Charisse M. Whiteside ◽  
MiMi P. Macias ◽  
Walter M. Kalback ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Loss ◽  
Transgenic Mouse Model ◽  
Frame Of Reference ◽  
Presenilin 1 ◽  
Rapid Synthesis ◽  
Aβ Peptides ◽  
Age Related ◽  
5Xfad Mice

Transgenic (Tg) mouse models of Alzheimer's disease (AD) have been extensively used to study the pathophysiology of this dementia and to test the efficacy of drugs to treat AD. The 5XFAD Tg mouse, which contains two presenilin-1 and three amyloid precursor protein (APP) mutations, was designed to rapidly recapitulate a portion of the pathologic alterations present in human AD. APP and its proteolytic peptides, as well as apolipoprotein E and endogenous mouse tau, were investigated in the 5XFAD mice at 3 months, 6 months, and 9 months. AD and nondemented subjects were used as a frame of reference. APP, amyloid-beta (Aβ) peptides, APP C-terminal fragments (CT99, CT83, AICD), β-site APP-cleaving enzyme, and APLP1 substantially increased with age in the brains of 5XFAD mice. Endogenous mouse tau did not show age-related differences. The rapid synthesis of Aβ and its impact on neuronal loss and neuroinflammation make the 5XFAD mice a desirable paradigm to model AD.

scholarly journals Mechanisms of Neuronal Death in the Cerebral Cortex during Aging and Development of Alzheimer’s Disease-Like Pathology in Rats

2019 ◽  
Vol 20 (22) ◽  
pp. 5632 ◽  
Author(s):  
Darya V. Telegina ◽  
Gleb K. Suvorov ◽  
Oyuna S. Kozhevnikova ◽  
Nataliya G. Kolosova
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Decision Making ◽  
Cell Death ◽  
Cerebral Cortex ◽  
Brain Development ◽  
Brain Region ◽  
Neuronal Death ◽  
Neuronal Loss ◽  
Decision Making Behavior

Alzheimer’s disease (AD) is the commonest type of late-life dementia and damages the cerebral cortex, a vulnerable brain region implicated in memory, emotion, cognition, and decision-making behavior. AD is characterized by progressive neuronal loss, but the mechanisms of cell death at different stages of the disease remain unknown. Here, by means of OXYS rats as an appropriate model of the most common (sporadic) AD form, we studied the main pathways of cell death during development of AD-like pathology, including the preclinical stage. We found that apoptosis is activated at the pre-symptomatic stage (age 20 days) correlating with the retardation of brain development in the OXYS strain early in life. Progression of the AD-like pathology was accompanied by activation of apoptosis and necroptosis resulting from a decline of autophagy-mediated proteostasis. Our results are consistent with the idea that the nature of changes in the pathways of apoptosis, autophagy, and necrosis depends on the stage of AD.

scholarly journals VGF-derived peptide TLQP-21 modulates microglial function through C3aR1 signaling pathways and reduces neuropathology in 5xFAD mice

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Farida El Gaamouch ◽  
Mickael Audrain ◽  
Wei-Jye Lin ◽  
Noam Beckmann ◽  
Cheng Jiang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rna Sequencing ◽  
Microglial Cells ◽  
Wild Type ◽  
Primary Microglia ◽  
Murine Microglia ◽  
5Xfad Mice ◽  
Transcriptomic Changes ◽  
Bv2 Microglial Cells

Abstract Background Multiomic studies by several groups in the NIH Accelerating Medicines Partnership for Alzheimer’s Disease (AMP-AD) identified VGF as a major driver of Alzheimer’s disease (AD), also finding that reduced VGF levels correlate with mean amyloid plaque density, Clinical Dementia Rating (CDR) and Braak scores. VGF-derived peptide TLQP-21 activates the complement C3a receptor-1 (C3aR1), predominantly expressed in the brain on microglia. However, it is unclear how mouse or human TLQP-21, which are not identical, modulate microglial function and/or AD progression. Methods We performed phagocytic/migration assays and RNA sequencing on BV2 microglial cells and primary microglia isolated from wild-type or C3aR1-null mice following treatment with TLQP-21 or C3a super agonist (C3aSA). Effects of intracerebroventricular TLQP-21 delivery were evaluated in 5xFAD mice, a mouse amyloidosis model of AD. Finally, the human HMC3 microglial cell line was treated with human TLQP-21 to determine whether specific peptide functions are conserved from mouse to human. Results We demonstrate that TLQP-21 increases motility and phagocytic capacity in murine BV2 microglial cells, and in primary wild-type but not in C3aR1-null murine microglia, which under basal conditions have impaired phagocytic function compared to wild-type. RNA sequencing of primary microglia revealed overlapping transcriptomic changes induced by treatment with TLQP-21 or C3a super agonist (C3aSA). There were no transcriptomic changes in C3aR1-null or wild-type microglia exposed to the mutant peptide TLQP-R21A, which does not activate C3aR1. Most of the C3aSA- and TLQP-21-induced differentially expressed genes were linked to cell migration and proliferation. Intracerebroventricular TLQP-21 administration for 28 days via implanted osmotic pump resulted in a reduction of amyloid plaques and associated dystrophic neurites and restored expression of subsets of Alzheimer-associated microglial genes. Finally, we found that human TLQP-21 activates human microglia in a fashion similar to activation of murine microglia by mouse TLQP-21. Conclusions These data provide molecular and functional evidence suggesting that mouse and human TLQP-21 modulate microglial function, with potential implications for the progression of AD-related neuropathology.

scholarly journals Deep proteome profiling of the hippocampus in the 5XFAD mouse model reveals biological process alterations and a novel biomarker of Alzheimer’s disease

2019 ◽  
Vol 51 (11) ◽  
pp. 1-17 ◽  
Author(s):  
Dong Kyu Kim ◽  
Dohyun Han ◽  
Joonho Park ◽  
Hyunjung Choi ◽  
Jong-Chan Park ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein S ◽  
Amyloid Plaque ◽  
Close Correlation ◽  
Differentially Expressed ◽  
Secretory Proteins ◽  
Wild Type ◽  
Plaque Deposition ◽  
5Xfad Mice

AbstractAlzheimer’s disease (AD), which is the most common type of dementia, is characterized by the deposition of extracellular amyloid plaques. To understand the pathophysiology of the AD brain, the assessment of global proteomic dynamics is required. Since the hippocampus is a major region affected in the AD brain, we performed hippocampal analysis and identified proteins that are differentially expressed between wild-type and 5XFAD model mice via LC-MS methods. To reveal the relationship between proteomic changes and the progression of amyloid plaque deposition in the hippocampus, we analyzed the hippocampal proteome at two ages (5 and 10 months). We identified 9,313 total proteins and 1411 differentially expressed proteins (DEPs) in 5- and 10-month-old wild-type and 5XFAD mice. We designated a group of proteins showing the same pattern of changes as amyloid beta (Aβ) as the Aβ-responsive proteome. In addition, we examined potential biomarkers by investigating secretory proteins from the Aβ-responsive proteome. Consequently, we identified vitamin K-dependent protein S (PROS1) as a novel microglia-derived biomarker candidate in the hippocampus of 5XFAD mice. Moreover, we confirmed that the PROS1 level in the serum of 5XFAD mice increases as the disease progresses. An increase in PROS1 is also observed in the sera of AD patients and shows a close correlation with AD neuroimaging markers in humans. Therefore, our quantitative proteome data obtained from 5XFAD model mice successfully predicted AD-related biological alterations and suggested a novel protein biomarker for AD.

scholarly journals O-GlcNAcylation ameliorates the pathological manifestations of Alzheimer’s disease by inhibiting necroptosis

2021 ◽  
Vol 7 (3) ◽  
pp. eabd3207
Author(s):  
Jinsu Park ◽  
Hee-Jin Ha ◽  
Eun Seon Chung ◽  
Seung Hyun Baek ◽  
Yoonsuk Cho ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Loss ◽  
Protective Role ◽  
Tau Pathology ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
5Xfad Mice ◽  
Ad Mouse Model ◽  
M2 Phenotype

O-GlcNAcylation (O-linked β-N-acetylglucosaminylation) is notably decreased in Alzheimer’s disease (AD) brain. Necroptosis is activated in AD brain and is positively correlated with neuroinflammation and tau pathology. However, the links among altered O-GlcNAcylation, β-amyloid (Aβ) accumulation, and necroptosis are unclear. Here, we found that O-GlcNAcylation plays a protective role in AD by inhibiting necroptosis. Necroptosis was increased in AD patients and AD mouse model compared with controls; however, decreased necroptosis due to O-GlcNAcylation of RIPK3 (receptor-interacting serine/threonine protein kinase 3) was observed in 5xFAD mice with insufficient O-linked β-N-acetylglucosaminase. O-GlcNAcylation of RIPK3 suppresses phosphorylation of RIPK3 and its interaction with RIPK1. Moreover, increased O-GlcNAcylation ameliorated AD pathology, including Aβ burden, neuronal loss, neuroinflammation, and damaged mitochondria and recovered the M2 phenotype and phagocytic activity of microglia. Thus, our data establish the influence of O-GlcNAcylation on Aβ accumulation and neurodegeneration, suggesting O-GlcNAcylation–based treatments as potential interventions for AD.

scholarly journals Centella asiatica Alters Metabolic Pathways Associated With Alzheimer’s Disease in the 5xFAD Mouse Model of ß-Amyloid Accumulation

2021 ◽  
Vol 12 ◽  
Author(s):  
Alex B. Speers ◽  
Manuel García-Jaramillo ◽  
Alicia Feryn ◽  
Donald G. Matthews ◽  
Talia Lichtenberg ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Metabolic Pathways ◽  
Centella Asiatica ◽  
Metabolomic Analysis ◽  
Wild Type ◽  
Amyloid Accumulation ◽  
5Xfad Mouse ◽  
5Xfad Mice ◽  
The Brain

Centella asiatica is an herb used in Ayurvedic and traditional Chinese medicine for its beneficial effects on brain health and cognition. Our group has previously shown that a water extract of Centella asiatica (CAW) elicits cognitive-enhancing effects in animal models of aging and Alzheimer’s disease, including a dose-related effect of CAW on memory in the 5xFAD mouse model of ß-amyloid accumulation. Here, we endeavor to elucidate the mechanisms underlying the effects of CAW in the brain by conducting a metabolomic analysis of cortical tissue from 5xFAD mice treated with increasing concentrations of CAW. Tissue was collected from 8-month-old male and female 5xFAD mice and their wild-type littermates treated with CAW (0, 200, 500, or 1,000 mg/kg/d) dissolved in their drinking water for 5 weeks. High-performance liquid chromatography coupled to high-resolution mass spectrometry analysis was performed and relative levels of 120 annotated metabolites were assessed in the treatment groups. Metabolomic analysis revealed sex differences in the effect of the 5xFAD genotype on metabolite levels compared to wild-type mice, and variations in the metabolomic response to CAW depending on sex, genotype, and CAW dose. In at least three of the four treated groups (5xFAD or wild-type, male or female), CAW (500 mg/kg/d) significantly altered metabolic pathways related to purine metabolism, nicotinate and nicotinamide metabolism, and glycerophospholipid metabolism. The results are in line with some of our previous findings regarding specific mechanisms of action of CAW (e.g., improving mitochondrial function, reducing oxidative stress, and increasing synaptic density). Furthermore, these findings provide new information about additional, potential mechanisms for the cognitive-enhancing effect of CAW, including upregulation of nicotinamide adenine dinucleotide in the brain and modulation of brain-derived neurotrophic factor. These metabolic pathways have been implicated in the pathophysiology of Alzheimer’s disease, highlighting the therapeutic potential of CAW in this neurodegenerative disease.

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