The neuroimmune axis of Alzheimer’s disease

Jorfi, Mehdi; Maaser-Hecker, Anna; Tanzi, Rudolph E.

doi:10.1186/s13073-023-01155-w

Cited by 107 publications

(85 citation statements)

References 332 publications

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“…The potential for T-cell infiltration into the brain with aging and AD has been a question in the field for at least a decade 83,84 . Aging causes an increase in CD8+ T-cells in mice 85 which has subsequently been characterized as tissue resident Tcells (Trm) but the characterization of infiltrating T-cells with aging and AD is an ongoing and controversial topic (for review see 84,[86][87][88] ). The data on T-cell infiltration into the parenchyma with non-pathological aging is varied with reports ranging from no or limited infiltration to significant numbers [89][90][91] .…”

Section: Discussionmentioning

confidence: 99%

Microglial MHC-I induction with aging and Alzheimer’s is conserved in mouse models and humans

Kellogg

Pham

Machalinski

et al. 2023

Preprint

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Major Histocompatibility Complex I (MHC-I) function in the CNS is still being determined after previously being thought to be absent from the brain. MHC-I expression increases with brain aging in mouse, rat, and human whole tissue analyses. Neuronal MHC-I expression has been proposed to regulate developmental synapse elimination and tau pathology in Alzheimer's disease (AD). However, the CNS cellular localization of MHC-I expression has been unclear. Across newly generated and publicly available ribosomal profiling, cell sorting, and single cell data, microglia were found to be the primary source of classical and non-classical MHC-I in mice and humans. TRAP-qPCR analysis of 3-6 m.o. and 18-22 m.o. mice revealed significant age-related induction of B2m, H2-D1, H2-K1, H2-M3, H2-Q6, and Tap1 in microglia but not in astrocytes and neurons. Across a timecourse from 12-23 m.o., microglial MHC-I gradually increases until 21 m.o. and then accelerates. MHC-I protein was also enriched in microglia and increased with aging. Expression of MHC-I binding Leukocyte Immunoglobulin-like (Lilr) and Paired immunoglobin-like type 2 (Pilr) receptors in microglia but not astrocytes or neurons opens the possibility of cell-autonomous signaling and are also increased with aging in mice and humans. Increased microglial MHC-I, Lilrs, and Pilrs were observed in mouse AD models and human data across numerous studies and in RNA-Seq of microglia from APP-PSEN1 mice. MHC-I expression occurred concurrently with p16 suggesting an association with cellular senescence. The conserved induction of MHC-I, Lilrs, and Pilrs with aging and AD open the possibility of cell-autonomous signaling to regulate microglial reactivation.

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Section: Discussionmentioning

confidence: 99%

Microglial MHC-I induction with aging and Alzheimer’s is conserved in mouse models and humans

Kellogg

Pham

Machalinski

et al. 2023

Preprint

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“…This has been seen for the ABCA7 and INPP5D genes, of which the latter is also a part of this module. INPP5D encodes for the SHIP1 protein, which has been implicated in AD 62,67 . It acts as a negative regulator of myeloid cell proliferation/survival and chemotaxis, immune cells homeostasis, it regulates macrophage programming, phagocytosis and activation, and neutrophil migration 68 .…”

Section: Resultsmentioning

confidence: 99%

“…Phagocytosis is decreased in this subtype 61 . Higher levels of T-cell infiltration are seen in AD patients, however, their exact role remains unclear 62 . The TFs of this module were IKZF1, NFATC2 and RUNX1.…”

Section: Functional Annotation Of the Modules Implicated Disruption I...mentioning

confidence: 99%

Comparative gene regulatory network analysis in Alzheimer’s disease and major depressive disorder

Puype

Deschildre

Vermeirssen

2023

Preprint

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Major depressive disorder and Alzheimer's disease are two prevalent and devastating disorders that still lack effective treatment. Despite distinct disease phenotypes, these two disorders are characterized by similar neuroinflammatory processes. However, it is not clear to what extent these processes are shared. To compare pathways and their regulators affected in Alzheimer's disease and depression, we adopted a systems biology approach. Consensus gene regulatory networks were built from RNA-seq data with GENIE3, CLR and Lemon-Tree. The two consensus networks were functionally characterized and compared to one another. Further, single-cell gene regulatory networks were constructed with SCENIC, to further characterize the regulatory programs active in specific cell types. In both disorders, aberrations in immune mechanisms and microglial activation were found, controlled by the same transcription factors (IKZF1, IRF8, NFATC2, RUNX1, SPI1, and TAL1). These transcription factors have been implicated in Alzheimer's disease before, while only one has been associated with depression hitherto. Moreover, in Alzheimer, dysfunctions in mitochondria, the proteasome and myelination were discovered. In depression, astrocyte function, GABA receptor signaling, and transport across the blood-brain barrier were aberrated. These disrupted pathways and transcription factors should be further investigated and might be used to develop novel therapies for neuroinflammatory disorders.

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“…While microglia are commonly known in neurodegeneration for their role in neuroinflammatory processes, and particularly contributing to Alzheimer’s disease pathology, 77 they have recently been implicated in cerebrovascular function. 78 A subpopulation of microglia, known as juxtavascular or capillary-associated microglia, 78 are located in close proximity of brain microvessels, specifically in direct contact with the capillary basement membrane without disrupting astrocytic endfeet or pericyte coverage of microvessels.…”

Section: Neurovascular Unit Dysfunctionmentioning

confidence: 99%

Basic Mechanisms of Brain Injury and Cognitive Decline in Hypertension

Baggeroer,

Cambronero,

Savan

et al. 2024

Hypertension

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Dementia affects almost 50 million adults worldwide, and remains a major cause of death and disability. Hypertension is a leading risk factor for dementia, including Alzheimer disease and Alzheimer disease–related dementias. Although this association is well-established, the mechanisms underlying hypertension-induced cognitive decline remain poorly understood. By exploring the mechanisms mediating the detrimental effects of hypertension on the brain, studies have aimed to provide therapeutic insights and strategies on how to protect the brain from the effects of blood pressure elevation. In this review, we focus on the basic mechanisms contributing to the cerebrovascular adaptions to elevated blood pressure and hypertension-induced microvascular injury. We also assess the cellular mechanisms of neurovascular unit dysfunction, focusing on the premise that cognitive impairment ensues when the dynamic metabolic demands of neurons are not met due to neurovascular uncoupling, and summarize cognitive deficits across various rodent models of hypertension as a resource for investigators. Despite significant advances in antihypertensive therapy, hypertension remains a critical risk factor for cognitive decline, and several questions remain about the development and progression of hypertension-induced cognitive impairment.

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The neuroimmune axis of Alzheimer’s disease

Cited by 107 publications

References 332 publications

Microglial MHC-I induction with aging and Alzheimer’s is conserved in mouse models and humans

Microglial MHC-I induction with aging and Alzheimer’s is conserved in mouse models and humans

Comparative gene regulatory network analysis in Alzheimer’s disease and major depressive disorder

Basic Mechanisms of Brain Injury and Cognitive Decline in Hypertension

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