Taylor R. Jay

TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models

Jay and colleagues show that TREM2 deficiency reduces the number of macrophages infiltrating the brain and is protective against disease pathogenesis in mouse models of Alzheimer’s disease.

Nuclear Receptors License Phagocytosis by Trem2+ Myeloid Cells in Mouse Models of Alzheimer's Disease

Alzheimers disease (AD) is characterized by a robust inflammatory response elicited by the accumulation and subsequent deposition of amyloid (Aβ) within the brain. The brains immune cells migrate to and invest their processes within Aβ plaques but are unable to efficiently phagocytose and clear plaques from the brain. Previous studies have shown that treatment of myeloid cells with nuclear receptor agonists increases expression of phagocytosis-related genes. In this study, we elucidate a novel mechanism by which nuclear receptors act to enhance phagocytosis in the AD brain. Treatment of murine models of AD with agonists of the nuclear receptors PPARγ, PPARδ, LXR, and RXR stimulated microglial phagocytosis in vitro and rapidly induced the expression of the phagocytic receptors Axl and MerTK. In murine models of AD, we found that plaque-associated macrophages expressed Axl and MerTK and treatment of the cells with an RXR agonist further induced their expression, coincident with the rapid reduction in plaque burden. Further characterization of MerTK+/Axl+ macrophages revealed that they also expressed the phagocytic receptor TREM2 and high levels of CD45, consistent with a peripheral origin of these cells. Importantly, in an ex vivo slice assay, nuclear receptor agonist treatment reversed the AD-related suppression of phagocytosis through a MerTK-dependent mechanism. Thus, nuclear receptor agonists increase MerTK and Axl expression on plaque-associated immune cells, consequently licensing their phagocytic activity and promoting plaque clearance.

Opposing Effects of Membrane-Anchored CX3CL1 on Amyloid and Tau Pathologies via the p38 MAPK Pathway

Several Alzheimers disease (AD) risk genes are specifically expressed by microglia within the CNS. However, the mechanisms by which microglia regulate the pathological hallmarks of AD—extracellular deposition of β-amyloid (Aβ) and intraneuronal hyperphosphorylation of microtubule-associated protein tau (MAPT)—remain to be established. Notably, deficiency for the microglial CX3CR1 receptor has opposing effects on Aβ and MAPT pathologies. CX3CL1, the neuronally derived cognate ligand for CX3CR1, signals both in membrane-anchored and soluble forms. In this study, we sought to determine the relative contribution on membrane-anchored versus soluble CX3CL1 in regulating the microglia-mediated amelioration of Aβ pathology, as well as provide insight into the potential downstream microglial-based mechanisms. As expected, CX3CL1 deficiency reduced Aβ deposition in APPPS1 animals in a similar manner to CX3CR1 deficiency. Surprisingly, however, CX3CL1-deficient APPPS1 animals exhibited enhanced neuronal MAPT phosphorylation despite reduced amyloid burden. Importantly, neither of these phenotypes was altered by transgenic expression of the soluble CX3CL1 isoform, suggesting that it is the membrane-anchored version of CX3CL1 that regulates microglial phagocytosis of Aβ and neuronal MAPT phosphorylation. Analysis of transcript levels in purified microglia isolated from APPPS1 mice with the various CX3CL1/CX3CR1 genotypes revealed increased expression of inflammatory cytokines and phagocytic markers, which was associated with activation of p38 mitogen-activated protein kinase and Aβ internalization within microglia. Together, these studies challenge the “frustrated phagocytosis” concept and suggest that neuronal–microglial communication link the two central AD pathologies.

The Evolving Biology of Microglia in Alzheimer’s Disease

Alzheimer’s disease (AD) is typified by a robust microglial-mediated inflammatory response within the brain. Indeed, microglial accumulation around plaques in AD is one of the classical hallmarks of the disease pathology. Although microglia have the capacity to remove β-amyloid deposits and alleviate disease pathology, they fail to do so. Instead, they become chronically activated and promote inflammation-mediated impairment of cognition and cytotoxicity. However, if microglial function could be altered to engage their phagocytic response, promote their tissue maintenance functions, and prevent release of factors that promote tissue damage, this could provide therapeutic benefit. This review is focused on the current knowledge of microglial homeostatic mechanisms in AD, and mechanisms involved in the regulation of microglial phenotype in this context.

Neuronally-directed effects of RXR activation in a mouse model of Alzheimer's disease

Alzheimer’s disease (AD) is characterized by extensive neuron loss that accompanies profound impairments in memory and cognition. We examined the neuronally directed effects of the retinoid X receptor agonist bexarotene in an aggressive model of AD. We report that a two week treatment of 3.5 month old 5XFAD mice with bexarotene resulted in the clearance of intraneuronal amyloid deposits. Importantly, neuronal loss was attenuated by 44% in the subiculum in mice 4 months of age and 18% in layer V of the cortex in mice 8 months of age. Moreover, bexarotene treatment improved remote memory stabilization in fear conditioned mice and improved olfactory cross habituation. These improvements in neuron viability and function were correlated with significant increases in the levels of post-synaptic marker PSD95 and the pre-synaptic marker synaptophysin. Moreover, bexarotene pretreatment improved neuron survival in primary 5XFAD neurons in vitro in response to glutamate-induced excitotoxicity. The salutary effects of bexarotene were accompanied by reduced plaque burden, decreased astrogliosis, and suppression of inflammatory gene expression. Collectively, these data provide evidence that bexarotene treatment reduced neuron loss, elevated levels of markers of synaptic integrity that was linked to improved cognition and in an aggressive model of AD.

THE R47H TREM2 VARIANT MODIFIES ALZHEIMER'S DISEASE PATHOLOGY AND NEUROINFLAMMATION IN A NOVEL KNOCK-IN MOUSE MODEL

Background:Microglia and associated neuroinflammation play a significant role in Alzheimer’s disease (AD). The voltage-gated potassium channel Kv1.3 (KCNA3) fine-tunes microglia activation by modulating Ca signaling. Because selective pharmacological targeting of Kv1.3 inmicroglia in the brain is feasible and safe, we tested the effects of a selective Kv1.3 blocker PAP-1 in models of AD.Methods: Human AD brains drawn from the brain repositories of the University of California Davis and the Emory University were used for immunohistochemical analyses ofKv1.3. 5xFADmice,which harbor three amyloid-b precursor protein (APP) and two presenilin-1 (PS1) mutations resulting in AD-like Ab amyloidosis and neuroinflammation, were used for behavioral, electrophysiological, biochemical and neuropathological analyses. Results: Kv1.3 immunoreactivities were localized exclusively to microglia in both human and mouse brains and were increased in human AD subjects and 5xFAD mice. Microglial Kv1.3 activity as measured by whole-cell patch-clamp was increased in young and middle-aged 5xFAD mice, but decreased in old (>13 months) 5xFAD mice compared to ageand gender-matched wildtype controls. Ab oligomers (AbO) were able to enhance microlgial Kv1.3 expression. PAP-1 treatment reduced AbO-induced microglial neurotoxicity in vitro and in vivo. A three-month oral regimen of PAP1 improved the hippocampus-dependent memory performance and rectified the hippocampal long-term potentiation of 5xFADmice.Conclusions:Microglial Kv1.3 is a potential therapeutic target and oral dosing of PAP-1 is a promising anti-inflammatory approach for AD.