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1.
Nat Aging ; 2(1): 60-73, 2022 01.
Article in English | MEDLINE | ID: mdl-37118355

ABSTRACT

Microglia and monocyte-derived macrophages (MDM) are key players in dealing with Alzheimer's disease. In amyloidosis mouse models, activation of microglia was found to be TREM2 dependent. Here, using Trem2-/-5xFAD mice, we assessed whether MDM act via a TREM2-dependent pathway. We adopted a treatment protocol targeting the programmed cell death ligand-1 (PD-L1) immune checkpoint, previously shown to modify Alzheimer's disease via MDM involvement. Blockade of PD-L1 in Trem2-/-5xFAD mice resulted in cognitive improvement and reduced levels of water-soluble amyloid beta1-42 with no effect on amyloid plaque burden. Single-cell RNA sequencing revealed that MDM, derived from both Trem2-/- and Trem2+/+5xFAD mouse brains, express a unique set of genes encoding scavenger receptors (for example, Mrc1, Msr1). Blockade of monocyte trafficking using anti-CCR2 antibody completely abrogated the cognitive improvement induced by anti-PD-L1 treatment in Trem2-/-5xFAD mice and similarly, but to a lesser extent, in Trem2+/+5xFAD mice. These results highlight a TREM2-independent, disease-modifying activity of MDM in an amyloidosis mouse model.


Subject(s)
Alzheimer Disease , Amyloidosis , Mice , Animals , Alzheimer Disease/genetics , Amyloid beta-Peptides/metabolism , Mice, Transgenic , Macrophages/metabolism , Amyloidosis/genetics , Membrane Glycoproteins/genetics , Receptors, Immunologic/genetics
2.
Nat Neurosci ; 23(6): 701-706, 2020 06.
Article in English | MEDLINE | ID: mdl-32341542

ABSTRACT

The role of non-neuronal cells in Alzheimer's disease progression has not been fully elucidated. Using single-nucleus RNA sequencing, we identified a population of disease-associated astrocytes in an Alzheimer's disease mouse model. These disease-associated astrocytes appeared at early disease stages and increased in abundance with disease progression. We discovered that similar astrocytes appeared in aged wild-type mice and in aging human brains, suggesting their linkage to genetic and age-related factors.


Subject(s)
Aging/pathology , Alzheimer Disease/pathology , Astrocytes/pathology , Brain/pathology , Hippocampus/pathology , Amyloid beta-Protein Precursor/genetics , Animals , Disease Progression , Female , Humans , Male , Mice , Mice, Transgenic
3.
Nat Commun ; 10(1): 465, 2019 01 28.
Article in English | MEDLINE | ID: mdl-30692527

ABSTRACT

Alzheimer's disease (AD) is a heterogeneous disorder with multiple etiologies. Harnessing the immune system by blocking the programmed cell death receptor (PD)-1 pathway in an amyloid beta mouse model was shown to evoke a sequence of immune responses that lead to disease modification. Here, blocking PD-L1, a PD-1 ligand, was found to have similar efficacy to that of PD-1 blocking in disease modification, in both animal models of AD and of tauopathy. Targeting PD-L1 in a tau-driven disease model resulted in increased immunomodulatory monocyte-derived macrophages within the brain parenchyma. Single cell RNA-seq revealed that the homing macrophages expressed unique scavenger molecules including macrophage scavenger receptor 1 (MSR1), which was shown here to be required for the effect of PD-L1 blockade in disease modification. Overall, our results demonstrate that immune checkpoint blockade targeting the PD-1/PD-L1 pathway leads to modification of common factors that go awry in AD and dementia, and thus can potentially provide an immunotherapy to help combat these diseases.


Subject(s)
B7-H1 Antigen/metabolism , Cognitive Dysfunction/metabolism , Macrophages/metabolism , Programmed Cell Death 1 Receptor/metabolism , Tauopathies/metabolism , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Animals , Antibodies, Blocking/pharmacology , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/immunology , Brain/immunology , Brain/metabolism , Cognitive Dysfunction/genetics , Disease Models, Animal , Humans , Macrophages/immunology , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred Strains , Mice, Transgenic , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Tauopathies/genetics
4.
Nat Commun ; 8(1): 717, 2017 09 28.
Article in English | MEDLINE | ID: mdl-28959042

ABSTRACT

During ageing, microglia acquire a phenotype that may negatively affect brain function. Here we show that ageing microglial phenotype is largely imposed by interferon type I (IFN-I) chronically present in aged brain milieu. Overexpression of IFN-ß in the CNS of adult wild-type mice, but not of mice lacking IFN-I receptor on their microglia, induces an ageing-like transcriptional microglial signature, and impairs cognitive performance. Furthermore, we demonstrate that age-related IFN-I milieu downregulates microglial myocyte-specific enhancer factor 2C (Mef2C). Immune challenge in mice lacking Mef2C in microglia results in an exaggerated microglial response and has an adverse effect on mice behaviour. Overall, our data indicate that the chronic presence of IFN-I in the brain microenvironment, which negatively affects cognitive function, is mediated via modulation of microglial activity. These findings may shed new light on other neurological conditions characterized by elevated IFN-I signalling in the brain.Microglia cells in the brain regulate immune responses, but in ageing can negatively affect brain function. Here the authors show that the chronic presence of type I interferon in aged mouse brain impedes cognitive ability by altering microglia transcriptome and limiting Mef2C, a microglia 'off' signal.


Subject(s)
Aging/immunology , Brain/immunology , Interferon-beta/immunology , MEF2 Transcription Factors/immunology , Microglia/immunology , Animals , Brain/growth & development , Brain/physiopathology , Humans , Interferon-beta/genetics , MEF2 Transcription Factors/genetics , Male , Mice , Mice, Inbred C57BL
5.
Cell ; 169(7): 1276-1290.e17, 2017 Jun 15.
Article in English | MEDLINE | ID: mdl-28602351

ABSTRACT

Alzheimer's disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, defining the roles of immune cell subsets in AD onset and progression has been challenging. Using transcriptional single-cell sorting, we comprehensively map all immune populations in wild-type and AD-transgenic (Tg-AD) mouse brains. We describe a novel microglia type associated with neurodegenerative diseases (DAM) and identify markers, spatial localization, and pathways associated with these cells. Immunohistochemical staining of mice and human brain slices shows DAM with intracellular/phagocytic Aß particles. Single-cell analysis of DAM in Tg-AD and triggering receptor expressed on myeloid cells 2 (Trem2)-/- Tg-AD reveals that the DAM program is activated in a two-step process. Activation is initiated in a Trem2-independent manner that involves downregulation of microglia checkpoints, followed by activation of a Trem2-dependent program. This unique microglia-type has the potential to restrict neurodegeneration, which may have important implications for future treatment of AD and other neurodegenerative diseases. VIDEO ABSTRACT.


Subject(s)
Alzheimer Disease/immunology , Alzheimer Disease/pathology , Microglia/pathology , Phagocytes/pathology , Alzheimer Disease/genetics , Animals , Humans , Mice , Mice, Transgenic , Microglia/metabolism , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/immunology , Neurodegenerative Diseases/pathology , Phagocytes/metabolism , Receptors, Immunologic/metabolism , Sequence Analysis, RNA , Single-Cell Analysis
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