CNS-Native Myeloid Cells Drive Immune Suppression in the Brain Metastatic Niche through Cxcl10.

Brain metastasis (br-met) develops in an immunologically unique br-met niche. Central nervous system-native myeloid cells (CNS-myeloids) and bone-marrow-derived myeloid cells (BMDMs) cooperatively regulate brain immunity. The phenotypic heterogeneity and specific roles of these myeloid subsets in shaping the br-met niche to regulate br-met outgrowth have not been fully revealed. Applying multimodal single-cell analyses, we elucidated a heterogeneous but spatially defined CNS-myeloid response during br-met outgrowth. We found Ccr2+ BMDMs minimally influenced br-met while CNS-myeloid promoted br-met outgrowth. Additionally, br-met-associated CNS-myeloid exhibited downregulation of Cx3cr1. Cx3cr1 knockout in CNS-myeloid increased br-met incidence, leading to an enriched interferon response signature and Cxcl10 upregulation. Significantly, neutralization of Cxcl10 reduced br-met, while rCxcl10 increased br-met and recruited VISTAHi PD-L1+ CNS-myeloid to br-met lesions. Inhibiting VISTA- and PD-L1-signaling relieved immune suppression and reduced br-met burden. Our results demonstrate that loss of Cx3cr1 in CNS-myeloid triggers a Cxcl10-mediated vicious cycle, cultivating a br-met-promoting, immune-suppressive niche.

Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer's disease.

Genetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimer's disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and functions in many immune receptor signaling pathways. In AD, PLCG2 is induced uniquely in plaque-associated microglia. A genetic variant of PLCG2, PLCG2P522R, is a mild hypermorph that attenuates AD risk. Here, we identified a loss-of-function PLCG2 variant, PLCG2M28L, that confers an increased AD risk. PLCG2P522R attenuated disease in an amyloidogenic murine AD model, whereas PLCG2M28L exacerbated the plaque burden associated with altered phagocytosis and Aß clearance. The variants bidirectionally modulated disease pathology by inducing distinct transcriptional programs that identified microglial subpopulations associated with protective or detrimental phenotypes. These findings identify PLCG2M28L as a potential AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted.

Deep learning-driven adaptive optics for single-molecule localization microscopy.

The inhomogeneous refractive indices of biological tissues blur and distort single-molecule emission patterns generating image artifacts and decreasing the achievable resolution of single-molecule localization microscopy (SMLM). Conventional sensorless adaptive optics methods rely on iterative mirror changes and image-quality metrics. However, these metrics result in inconsistent metric responses and thus fundamentally limit their efficacy for aberration correction in tissues. To bypass iterative trial-then-evaluate processes, we developed deep learning-driven adaptive optics for SMLM to allow direct inference of wavefront distortion and near real-time compensation. Our trained deep neural network monitors the individual emission patterns from single-molecule experiments, infers their shared wavefront distortion, feeds the estimates through a dynamic filter and drives a deformable mirror to compensate sample-induced aberrations. We demonstrated that our method simultaneously estimates and compensates 28 wavefront deformation shapes and improves the resolution and fidelity of three-dimensional SMLM through >130-µm-thick brain tissue specimens.

Control of the temporal development of Alzheimer's disease pathology by the MR1/MAIT cell axis.

BACKGROUND: Neuroinflammation is an important feature of Alzheimer's disease (AD). Understanding which aspects of the immune system are important in AD may lead to new therapeutic approaches. We study the major histocompatibility complex class I-related immune molecule, MR1, which is recognized by an innate-like T cell population called mucosal-associated invariant T (MAIT) cells. METHODS: Having found that MR1 gene expression is elevated in the brain tissue of AD patients by mining the Agora database, we sought to examine the role of the MR1/MAIT cell axis in AD pathology. Brain tissue from AD patients and the 5XFAD mouse model of AD were used to analyze MR1 expression through qPCR, immunofluorescence, and flow cytometry. Furthermore, mice deficient in MR1 and MAIT cells were crossed with the 5XFAD mice to produce a model to study how the loss of this innate immune axis alters AD progression. Moreover, 5XFAD mice were also used to study brain-resident MAIT cells over time. RESULTS: In tissue samples from AD patients and 5XFAD mice, MR1 expression was substantially elevated in the microglia surrounding plaques vs. those that are further away (human AD: P < 0.05; 5XFAD: P < 0.001). In 5XFAD mice lacking the MR1/MAIT cell axis, the development of amyloid-beta plaque pathology occurred at a significantly slower rate than in those mice with MR1 and MAIT cells. Furthermore, in brain tissue from 5XFAD mice, there was a temporal increase in MAIT cell numbers (P < 0.01) and their activation state, the latter determined by detecting an upregulation of both CD69 (P < 0.05) and the interleukin-2 receptor alpha chain (P < 0.05) via flow cytometry. CONCLUSIONS: Together, these data reveal a previously unknown role for the MR1/MAIT cell innate immune axis in AD pathology and its potential utility as a novel therapeutic target.

Three-dimensional nanoscopy of whole cells and tissues with in situ point spread function retrieval.

Single-molecule localization microscopy is a powerful tool for visualizing subcellular structures, interactions and protein functions in biological research. However, inhomogeneous refractive indices inside cells and tissues distort the fluorescent signal emitted from single-molecule probes, which rapidly degrades resolution with increasing depth. We propose a method that enables the construction of an in situ 3D response of single emitters directly from single-molecule blinking datasets, and therefore allows their locations to be pinpointed with precision that achieves the Cramér-Rao lower bound and uncompromised fidelity. We demonstrate this method, named in situ PSF retrieval (INSPR), across a range of cellular and tissue architectures, from mitochondrial networks and nuclear pores in mammalian cells to amyloid-ß plaques and dendrites in brain tissues and elastic fibers in developing cartilage of mice. This advancement expands the routine applicability of super-resolution microscopy from selected cellular targets near coverslips to intra- and extracellular targets deep inside tissues.

Integrating multimodality magnetic resonance imaging to the Allen Mouse Brain Common Coordinate Framework.

High-resolution magnetic resonance imaging (MRI) affords unique image contrasts to nondestructively probe the tissue microstructure; validation of MRI findings with conventional histology is essential to better understand the MRI contrasts. However, the dramatic difference in the spatial resolution and image contrast of these two techniques impedes accurate comparison between MRI metrics and traditional histology. To better validate various MRI metrics, we acquired whole mouse brain multigradient recalled-echo and multishell diffusion MRI datasets at 25-µm isotropic resolution. The recently developed Allen Mouse Brain Common Coordinate Framework (CCFv3) provides opportunities to integrate multimodal and multiscale datasets of the whole mouse brain in a common three-dimensional (3D) space. The T2*, quantitative susceptibility mapping, diffusion tensor imaging, and neurite orientation dispersion and density imaging parameters were compared with both serial two-photon tomography images and 3D Nissl staining images in the CCFv3 at the same spatial resolution. The correlation between MRI and Nissl staining strongly depends on different metrics and different regions of the brain. Integrating different imaging modalities to the same space may substantially improve our understanding of the complexity of the brain at different scales.

INPP5D deficiency attenuates amyloid pathology in a mouse model of Alzheimer's disease.

INTRODUCTION: Inositol polyphosphate-5-phosphatase (INPP5D) is a microglia-enriched lipid phosphatase in the central nervous system. A non-coding variant (rs35349669) in INPP5D increases the risk for Alzheimer's disease (AD), and elevated INPP5D expression is associated with increased plaque deposition. INPP5D negatively regulates signaling via several microglial cell surface receptors, including triggering receptor expressed on myeloid cells 2 (TREM2); however, the impact of INPP5D inhibition on AD pathology remains unclear. METHODS: We used the 5xFAD mouse model of amyloidosis to assess how Inpp5d haplodeficiency regulates amyloid pathogenesis. RESULTS: Inpp5d haplodeficiency perturbs the microglial intracellular signaling pathways regulating the immune response, including phagocytosis and clearing of amyloid beta (Aß). It is important to note that Inpp5d haploinsufficiency leads to the preservation of cognitive function. Spatial transcriptomic analysis revealed that pathways altered by Inpp5d haploinsufficiency are related to synaptic regulation and immune cell activation. CONCLUSION: These data demonstrate that Inpp5d haplodeficiency enhances microglial functions by increasing plaque clearance and preserves cognitive abilities in 5xFAD mice. Inhibition of INPP5D is a potential therapeutic strategy for AD.

Nuclear Receptors as Therapeutic Targets for Neurodegenerative Diseases: Lost in Translation.

Neurodegenerative diseases are characterized by a progressive loss of neurons that leads to a broad range of disabilities, including severe cognitive decline and motor impairment, for which there are no effective therapies. Several lines of evidence support a putative therapeutic role of nuclear receptors (NRs) in these types of disorders. NRs are ligand-activated transcription factors that regulate the expression of a wide range of genes linked to metabolism and inflammation. Although the activation of NRs in animal models of neurodegenerative disease exhibits promising results, the translation of this strategy to clinical practice has been unsuccessful. In this review we discuss the role of NRs in neurodegenerative diseases in light of preclinical and clinical studies, as well as new findings derived from the analysis of transcriptomic databases from humans and animal models. We discuss the failure in the translation of NR-based therapeutic approaches and consider alternative and novel research avenues in the development of effective therapies for neurodegenerative diseases.

The P522R protective variant of PLCG2 promotes the expression of antigen presentation genes by human microglia in an Alzheimer's disease mouse model.

The P522R variant of PLCG2, expressed by microglia, is associated with reduced risk of Alzheimer's disease (AD). Yet, the impact of this protective mutation on microglial responses to AD pathology remains unknown. Chimeric AD and wild-type mice were generated by transplanting PLCG2-P522R or isogenic wild-type human induced pluripotent stem cell microglia. At 7 months of age, single-cell and bulk RNA sequencing, and histological analyses were performed. The PLCG2-P522R variant induced a significant increase in microglial human leukocyte antigen (HLA) expression and the induction of antigen presentation, chemokine signaling, and T cell proliferation pathways. Examination of immune-intact AD mice further demonstrated that the PLCG2-P522R variant promotes the recruitment of CD8+ T cells to the brain. These data provide the first evidence that the PLCG2-P522R variant increases the capacity of microglia to recruit T cells and present antigens, promoting a microglial transcriptional state that has recently been shown to be reduced in AD patient brains.

INPP5D expression is associated with risk for Alzheimer's disease and induced by plaque-associated microglia.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, robust microgliosis, neuroinflammation, and neuronal loss. Genome-wide association studies recently highlighted a prominent role for microglia in late-onset AD (LOAD). Specifically, inositol polyphosphate-5-phosphatase (INPP5D), also known as SHIP1, is selectively expressed in brain microglia and has been reported to be associated with LOAD. Although INPP5D is likely a crucial player in AD pathophysiology, its role in disease onset and progression remains unclear. We performed differential gene expression analysis to investigate INPP5D expression in AD and its association with plaque density and microglial markers using transcriptomic (RNA-Seq) data from the Accelerating Medicines Partnership for Alzheimer's Disease (AMP-AD) cohort. We also performed quantitative real-time PCR, immunoblotting, and immunofluorescence assays to assess INPP5D expression in the 5xFAD amyloid mouse model. Differential gene expression analysis found that INPP5D expression was upregulated in LOAD and positively correlated with amyloid plaque density. In addition, in 5xFAD mice, Inpp5d expression increased as the disease progressed, and selectively in plaque-associated microglia. Increased Inpp5d expression levels in 5xFAD mice were abolished entirely by depleting microglia with the colony-stimulating factor receptor-1 antagonist PLX5622. Our findings show that INPP5D expression increases as AD progresses, predominantly in plaque-associated microglia. Importantly, we provide the first evidence that increased INPP5D expression might be a risk factor in AD, highlighting INPP5D as a potential therapeutic target. Moreover, we have shown that the 5xFAD mouse model is appropriate for studying INPP5D in AD.

Active PSF shaping and adaptive optics enable volumetric localization microscopy through brain sections.

Application of single-molecule switching nanoscopy (SMSN) beyond the coverslip surface poses substantial challenges due to sample-induced aberrations that distort and blur single-molecule emission patterns. We combined active shaping of point spread functions and efficient adaptive optics to enable robust 3D-SMSN imaging within tissues. This development allowed us to image through 30-µm-thick brain sections to visualize and reconstruct the morphology and the nanoscale details of amyloid-ß filaments in a mouse model of Alzheimer's disease.

PMP22 Regulates Cholesterol Trafficking and ABCA1-Mediated Cholesterol Efflux.

The absence of functional peripheral myelin protein 22 (PMP22) is associated with shortened lifespan in rodents and severe peripheral nerve myelin abnormalities in several species including humans. Schwann cells and nerves from PMP22 knock-out (KO) mice show deranged cholesterol distribution and aberrant lipid raft morphology, supporting an unrecognized role for PMP22 in cellular lipid metabolism. To examine the mechanisms underlying these abnormalities, we studied Schwann cells and nerves from male and female PMP22 KO mice. Whole-cell current-clamp recordings in cultured Schwann cells revealed increased membrane capacitance and decreased membrane resistance in the absence of PMP22, which was consistent with a reduction in membrane cholesterol. Nerves from PMP22-deficient mice contained abnormal lipid droplets, with both mRNA and protein levels of apolipoprotein E (apoE) and ATP-binding cassette transporter A1 (ABCA1) being highly upregulated. Despite the upregulation of ABCA1 and apoE, the absence of PMP22 resulted in reduced localization of the transporter to the cell membrane and diminished secretion of apoE. The absence of PMP22 also impaired ABCA1-mediated cholesterol efflux capacity. In nerves from ABCA1 KO mice, the expression of PMP22 was significantly elevated and the subcellular processing of the overproduced protein was aberrant. In wild-type samples, double immunolabeling identified overlapping distribution of PMP22 and ABCA1 at the Schwann cell plasma membrane and the two proteins were coimmunoprecipitated from Schwann cell and nerve lysates. Together, these results reveal a novel role for PMP22 in regulating lipid metabolism and cholesterol trafficking through functional interaction with the cholesterol efflux regulatory protein ABCA1.SIGNIFICANCE STATEMENT Understanding the subcellular events that underlie abnormal myelin formation in hereditary neuropathies is critical for advancing therapy development. Peripheral myelin protein 22 (PMP22) is an essential peripheral myelin protein because its genetic abnormalities account for ∼80% of hereditary neuropathies. Here, we demonstrate that in the absence of PMP22, the cellular and electrophysiological properties of the Schwann cells' plasma membrane are altered and cholesterol trafficking and lipid homeostasis are perturbed. The molecular mechanisms for these abnormalities involve a functional interplay among PMP22, cholesterol, apolipoprotein E, and the major cholesterol-efflux transporter protein ATP-binding cassette transporter A1 (ABCA1). These findings establish a critical role for PMP22 in the maintenance of cholesterol homeostasis in Schwann cells.

The effect of amyloid on microglia-neuron interactions before plaque onset occurs independently of TREM2 in a mouse model of Alzheimer's disease.

Genetic studies identified mutations in several immune-related genes that confer increased risk for developing Alzheimer's disease (AD), suggesting a key role for microglia in AD pathology. Microglia are recruited to and actively modulate the local toxicity of amyloid plaques in models of AD through these cells' transcriptional and functional reprogramming to a disease-associated phenotype. However, it remains unknown whether microglia actively respond to amyloid accumulation before plaque deposition in AD. We compared microglial interactions with neurons that exhibit amyloid accumulation to those that do not in 1-month-old 5XFAD mice to determine which aspects of microglial morphology and function are altered by early 6E10+ amyloid accumulation. We provide evidence of preferential microglial process engagement of amyloid laden neurons. Microglia, on exposure to amyloid, also increase their internalization of neurites even before plaque onset. Unexpectedly, we found that triggering receptor expressed on myeloid cells 2 (TREM2), which is critical for microglial responses to amyloid plaque pathology later in disease, is not required for enhanced microglial interactions with neurons or neurite internalization early in disease. However, TREM2 was still required for early morphological changes exhibited by microglia. These data demonstrate that microglia sense and respond to amyloid accumulation before plaques form using a distinct mechanism from the TREM2-dependent pathway required later in disease.

Microglia depletion rapidly and reversibly alters amyloid pathology by modification of plaque compaction and morphologies.

Alzheimer's disease (AD) is a prominent neurodegenerative disorder characterized by deposition of ß-amyloid (Aß)-containing extracellular plaques, accompanied by a microglial-mediated inflammatory response, that leads to cognitive decline. Microglia perform many disease-modifying functions such as phagocytosis of plaques, plaque compaction, and modulation of inflammation through the secretion of cytokines. Microglia are reliant upon colony-stimulating factor receptor-1 (CSF1R) activation for survival. In AD mouse models, chronic targeted depletion of microglia via CSF1R antagonism attenuates plaque formation in early disease but fails to alter plaque burden in late disease. It is unclear if acute depletion of microglia during the peak period of plaque deposition will alter disease pathogenesis, and if so, whether these effects are reversible upon microglial repopulation. To test this, we administered the CSF1R antagonist PLX5622 to the 5XFAD mouse model of AD at four months of age for approximately one month. In a subset of mice, the drug treatment was discontinued, and the mice were fed a control diet for an additional month. We evaluated plaque burden and composition, microgliosis, inflammatory marker expression, and neuritic dystrophy. In 5XFAD animals, CSF1R blockade for 28 days depleted microglia across brain regions by over 50%, suppressed microgliosis, and reduced plaque burden. In microglial-depleted AD animals, neuritic dystrophy was enhanced, and increased diffuse-like plaques and fewer compact-like plaques were observed. Removal of PLX5622 elicited microglial repopulation and subsequent plaque remodeling, resulting in more compact plaques predominating microglia-repopulated regions. We found that microglia limit diffuse plaques by maintaining compact-like plaque properties, thereby blocking the progression of neuritic dystrophy. Microglial repopulation reverses these effects. Collectively, we show that microglia are neuroprotective through maintenance of plaque compaction and morphologies during peak disease progression.

Pharmacological Inhibition of ERK Signaling Rescues Pathophysiology and Behavioral Phenotype Associated with 16p11.2 Chromosomal Deletion in Mice.

The human 16p11.2 microdeletion is one of the most common gene copy number variations linked to autism, but the pathophysiology associated with this chromosomal abnormality is largely unknown. The 593 kb deletion contains the ERK1 gene and other genes that converge onto the ERK/MAP kinase pathway. Perturbations in ERK signaling are linked to a group of related neurodevelopmental disorders hallmarked by intellectual disability, including autism. We report that mice harboring the 16p11.2 deletion exhibit a paradoxical elevation of ERK activity, cortical cytoarchitecture abnormalities and behavioral deficits. Importantly, we show that treatment with a novel ERK pathway inhibitor during a critical period of brain development rescues the molecular, anatomical and behavioral deficits in the 16p11.2 deletion mice. The ERK inhibitor treatment administered to adult mice ameliorates a subset of these behavioral deficits. Our findings provide evidence for potential targeted therapeutic intervention in 16p11.2 deletion carriers.SIGNIFICANCE STATEMENT The ERK/MAPK pathway is genetically linked to autism spectrum disorders and other syndromes typified by intellectual disability. We provide direct evidence connecting the ERK/MAP kinases to the developmental abnormalities in neurogenesis and cortical cytoarchitecture associated with the 16p11.2 chromosomal deletion. Most importantly, we demonstrate that treatment with a novel ERK-specific inhibitor during development rescues aberrant cortical cytoarchitecture and restores normal levels of cell-cycle regulators during cortical neurogenesis. These treatments partially reverse the behavioral deficits observed in the 16p11.2del mouse model, including hyperactivity, memory as well as olfaction, and maternal behavior. We also report a rescue of a subset of these deficits upon treatment of adult 16p11.2del mice. These data provide a strong rationale for therapeutic approaches to this disorder.

TREM2 is required for microglial instruction of astrocytic synaptic engulfment in neurodevelopment.

Variants in the microglial receptor TREM2 confer risk for multiple neurodegenerative diseases. However, it remains unknown how this receptor functions on microglia to modulate these diverse neuropathologies. To understand the role of TREM2 on microglia more generally, we investigated changes in microglial function in Trem2-/- mice. We found that loss of TREM2 impairs normal neurodevelopment, resulting in reduced synapse number across the cortex and hippocampus in 1-month-old mice. This reduction in synapse number was not due directly to alterations in interactions between microglia and synapses. Rather, TREM2 was required for microglia to limit synaptic engulfment by astrocytes during development. While these changes were largely normalized later in adulthood, high fat diet administration was sufficient to reinitiate TREM2-dependent modulation of synapse loss. Together, this identifies a novel role for microglia in instructing synaptic pruning by astrocytes to broadly regulate appropriate synaptic refinement, and suggests novel candidate mechanisms for how TREM2 and microglia could influence synaptic loss in brain injury and disease.

PPARß/δ-agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1ΔE9 astrocytes.

Astrocytes are the gatekeepers of neuronal energy supply. In neurodegenerative diseases, bioenergetics demand increases and becomes reliant upon fatty acid oxidation as a source of energy. Defective fatty acid oxidation and mitochondrial dysfunctions correlate with hippocampal neurodegeneration and memory deficits in Alzheimer's disease (AD), but it is unclear whether energy metabolism can be targeted to prevent or treat the disease. Here we show for the first time an impairment in fatty acid oxidation in human astrocytes derived from induced pluripotent stem cells of AD patients. The impairment was corrected by treatment with a synthetic peroxisome proliferator activated receptor delta (PPARß/δ) agonist GW0742 which acts to regulate an array of genes governing cellular metabolism. GW0742 enhanced the expression of CPT1a, the gene encoding for a rate-limiting enzyme of fatty acid oxidation. Similarly, treatment of a mouse model of AD, the APP/PS1-mice, with GW0742 increased the expression of Cpt1a and concomitantly reversed memory deficits in a fear conditioning test. Although the GW0742-treated mice did not show altered astrocytic glial fibrillary acidic protein-immunoreactivity or reduction in amyloid beta (Aß) load, GW0742 treatment increased hippocampal neurogenesis and enhanced neuronal differentiation of neuronal progenitor cells. Furthermore, GW0742 prevented Aß-induced impairment of long-term potentiation in hippocampal slices. Collectively, these data suggest that PPARß/δ-agonism alleviates AD related deficits through increasing fatty acid oxidation in astrocytes and improves cognition in a transgenic mouse model of AD.

Disease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer's Disease.

Neuroinflammation is an important contributor to Alzheimer's disease (AD) pathogenesis, as underscored by the recent identification of immune-related genetic risk factors for AD, including coding variants in the gene TREM2 (triggering receptor expressed on myeloid cells 2). Understanding TREM2 function promises to provide important insights into how neuroinflammation contributes to AD pathology. However, studies so far have produced seemingly conflicting results, with reports that amyloid pathology can be both decreased and increased in TREM2-deficient AD mouse models. In this study, we unify these previous findings by demonstrating that TREM2 deficiency ameliorates amyloid pathology early, but exacerbates it late in disease progression in the APPPS1-21 mouse model of AD. We also demonstrate that TREM2 deficiency decreases plaque-associated myeloid cell accumulation by reducing cell proliferation, specifically late in pathology. In addition, TREM2 deficiency reduces myeloid cell internalization of amyloid throughout pathology, but decreases inflammation-related gene transcript levels selectively late in disease progression. Together, these results suggest that TREM2 plays distinct functional roles at different stages in AD pathology. SIGNIFICANCE STATEMENT: Alzheimer's disease (AD) is a devastating neurodegenerative disorder and there are currently no effective treatments that modify disease progression. However, the recent identification of genetic risk factors for AD promises to provide new insight into AD biology and possible new therapeutic targets. Among these risk factors, variants in the gene TREM2 (triggering receptor expressed on myeloid cells 2) confer greatly elevated risk for developing the disease. We demonstrate that TREM2 deficiency has opposing effects on AD-related pathologies at early and late stages of disease progression, unifying previous work in the field. In addition, we examine how TREM2 affects the function of the brain immune cell populations in which it is expressed throughout disease progression to understand possible mechanisms underlying its differential impacts on pathology.

Nuclear receptor agonist-driven modification of inflammation and amyloid pathology enhances and sustains cognitive improvements in a mouse model of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a highly prevalent neurodegenerative disorder characterized by pathological hallmarks of beta-amyloid plaque deposits, tau pathology, inflammation, and cognitive decline. Treatment remains a clinical obstacle due to lack of effective therapeutics. Agonists targeting nuclear receptors, such as bexarotene, reversed cognitive deficits regardless of treatment duration and age in murine models of AD. While bexarotene demonstrated marked efficacy in decreasing plaque levels following short-term treatment, prolonged treatment did not modulate plaque burden. This suggested that plaques might reform in mice treated chronically with bexarotene and that cessation of bexarotene treatment before plaques reform might alter amyloid pathology, inflammation, and cognition in AD mice. METHODS: We utilized one-year-old APP/PS1 mice that were divided into two groups. We treated one group of mice for 2 weeks with bexarotene. The other group of mice was treated for 2 weeks with bexarotene followed by withdrawal of drug treatment for an additional 2 weeks. Cognition was evaluated using the novel-object recognition test either at the end of bexarotene treatment or the end of the withdrawal period. We then analyzed amyloid pathology and microgliosis at the conclusion of the study in both groups. RESULTS: Bexarotene treatment enhanced cognition in APP/PS1 mice similar to previous findings. Strikingly, we observed sustained cognitive improvements in mice in which bexarotene treatment was discontinued for 2 weeks. We observed a sustained reduction in microgliosis and plaque burden following drug withdrawal exclusively in the hippocampus. CONCLUSIONS: Our findings demonstrate that bexarotene selectively modifies aspects of neuroinflammation in a region-specific manner to reverse hippocampal-dependent cognitive deficits in AD mice and may provide insight to inform future studies with nuclear receptor agonists.

Therapeutic potential of nuclear receptor agonists in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by an extensive accumulation of amyloid-ß (Aß) peptide, which triggers a set of deleterious processes, including synaptic dysfunction, inflammation, and neuronal injury, leading to neuronal loss and cognitive impairment. A large body of evidence supports that nuclear receptor (NR) activation could be a promising therapeutic approach for AD. NRs are ligand-activated transcription factors that regulate gene expression and have cell type-specific effects. In this review, we discuss the mechanisms that underlie the beneficial effects of NRs in AD. Moreover, we summarize studies reported in the last 10-15 years and their major outcomes arising from the pharmacological targeting of NRs in AD animal models. The dissection of the pathways regulated by NRs in the context of AD is of importance in identifying novel and effective therapeutic strategies.