https://www.cell.com/cell/pdf/S0092-8674(19)31007-4.pdf

Alzheimer Disease: An Update on Pathobiology and Treatment Strategies.

/pdf/inflammation-as-a-central-mechanism-in-alzheimer-s-disease-eiiqrx1far.pdf

Inflammation as a central mechanism in Alzheimer's disease

Microglia are yolk sac-derived macrophages residing in the parenchyma of brain and spinal cord, where they interact with neurons and other glial. After different conditioning paradigms and bone marrow (BM) or hematopoietic stem cell (HSC) transplantation, graft-derived cells seed the brain and persistently contribute to the parenchymal brain macrophage compartment. Here we establish that graft-derived macrophages acquire, over time, microglia characteristics, including ramified morphology, longevity, radio-resistance and clonal expansion. However, even after prolonged CNS residence, transcriptomes and chromatin accessibility landscapes of engrafted, BM-derived macrophages remain distinct from yolk sac-derived host microglia. Furthermore, engrafted BM-derived cells display discrete responses to peripheral endotoxin challenge, as compared to host microglia. In human HSC transplant recipients, engrafted cells also remain distinct from host microglia, extending our finding to clinical settings. Collectively, our data emphasize the molecular and functional heterogeneity of parenchymal brain macrophages and highlight potential clinical implications for HSC gene therapies aimed to ameliorate lysosomal storage disorders, microgliopathies or general monogenic immuno-deficiencies. Irradiation depletes brain microglia cells and induces replenishment of the pool by bone marrow (BM)-derived macrophage. Here the authors show, using mouse BM chimera, that BM-derived macrophages establish long-term residency in the brain, but remain distinct from resident microglia in their transcriptome and gene accessibility landscape.

/pdf/engrafted-parenchymal-brain-macrophages-differ-from-fo8sgg3rht.pdf

Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge

Microglia Biology: One Century of Evolving Concepts.

Microglia are the primary innate immune cells in the CNS In the healthy brain, they exhibit a unique molecular homeostatic 'signature', consisting of a specific transcriptional profile and surface protein expression pattern, which differs from that of tissue macrophages In recent years, there have been a number of important advances in our understanding of the molecular signatures of homeostatic microglia and disease-associated microglia that have provided insight into how these cells are regulated in health and disease and how they contribute to the maintenance of the neural environment

/pdf/microglial-signatures-and-their-role-in-health-and-disease-5afxfhkbj9.pdf

Microglial signatures and their role in health and disease

Cerebral blood flow is reduced early in Alzheimer’s disease (AD). Because most of the vascular resistance within the brain is in capillaries, this could reflect dysfunction of contractile pericytes on capillary walls. Here we used live and rapidly-fixed biopsied human tissue to establish disease-relevance, and rodent experiments to define mechanism. We found that, in humans with cognitive decline, amyloid β (Aβ) constricts brain capillaries at pericyte locations. This was caused by Aβ generating reactive oxygen species, which evoked the release of endothelin-1 (ET) that activated pericyte ETA receptors. Capillary, but not arteriole, constriction also occurred in vivo in a mouse model of AD. Thus, inhibiting the capillary constriction caused by Aβ could potentially reduce energy lack and neurodegeneration in AD.

/pdf/amyloid-b-oligomers-constrict-human-capillaries-in-alzheimer-2eg928zbpy.pdf

Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes

Microglial Ramification, Surveillance, and Interleukin-1β Release Are Regulated by the Two-Pore Domain K+ Channel THIK-1

Receptors, Ion Channels, and Signaling Mechanisms Underlying Microglial Dynamics

Ion Channels and Receptors as Determinants of Microglial Function.

Neuronal gap junctional hemichannels, composed of pannexin-1 subunits, have been suggested to play a crucial role in epilepsy and brain ischaemia. After a few minutes of anoxia or ischaemia, neurons in brain slices show a rapid depolarization to ∼−20 mV, called the anoxic depolarization. Glutamate receptor blockers can prevent the anoxic depolarization, suggesting that it is produced by a cation influx through glutamate-gated channels. However, in isolated hippocampal pyramidal cells, simulated ischaemia evokes a large inward current and an increase in permeability to large molecules, mediated by the opening of pannexin-1 hemichannels. N -methyl-d-aspartate is also reported to open these hemichannels, suggesting that the activation of N -methyl-d-aspartate receptors, which occurs when glutamate is released in ischaemia, might cause the anoxic depolarization by evoking a secondary ion flux through pannexin-1 hemichannels. We tested the contribution of pannexin hemichannels to the anoxic depolarization in CA1 pyramidal cells in the more physiological environment of hippocampal slices. Three independent inhibitors of hemichannels—carbenoxolone, lanthanum and mefloquine—had no significant effect on the current generating the anoxic depolarization, while a cocktail of glutamate and gamma-aminobutyric acid class A receptor blockers abolished it. We conclude that pannexin hemichannels do not generate the large inward current that underlies the anoxic depolarization. Glutamate receptor channels remain the main candidate for generating the large inward current that produces the anoxic depolarization.

* Abbreviations
 : AMPA 
 :  α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate
 GABA 
 :  gamma-aminobutyric acid
 GABAA 
 :  gamma-aminobutyric acid class A
 NMDA 
 : N -methyl-d-aspartate

/pdf/the-role-of-pannexin-hemichannels-in-the-anoxic-4jzmt6qbnb.pdf

Christian Madry

Papers

Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes

Microglial Ramification, Surveillance, and Interleukin-1β Release Are Regulated by the Two-Pore Domain K+ Channel THIK-1

Receptors, Ion Channels, and Signaling Mechanisms Underlying Microglial Dynamics

Ion Channels and Receptors as Determinants of Microglial Function.

The role of pannexin hemichannels in the anoxic depolarization of hippocampal pyramidal cells