Diet-induced metabolic and immune impairments are sex-specifically modulated by soluble TNF signaling in the 5xFAD mouse model of Alzheimer's disease.

Emerging evidence indicates that high-fat, high carbohydrate diet (HFHC) impacts central pathological features of Alzheimer's disease (AD) across both human incidences and animal models. However, the mechanisms underlying this association are poorly understood. Here, we identify compartment-specific metabolic and inflammatory dysregulations that are induced by HFHC diet in the 5xFAD mouse model of AD pathology. We observe that both male and female 5xFAD mice display exacerbated adiposity, cholesterolemia, and dysregulated insulin signaling. Independent of biological sex, HFHC diet also resulted in altered inflammatory cytokine profiles across the gastrointestinal, circulating, and central nervous systems (CNS) compartments demonstrating region-specific impacts of metabolic inflammation. Interestingly, inhibiting the inflammatory cytokine, soluble tumor necrosis factor (TNF) with the brain-permeant soluble TNF inhibitor XPro1595 was able to restore aspects of HFHC-induced metabolic inflammation, but only in male mice. Targeted transcriptomics of CNS regions revealed that inhibition of soluble TNF was sufficient to alter expression of hippocampal and cortical genes associated with beneficial immune and metabolic responses. Collectively, these results suggest that HFHC diet impairs metabolic and inflammatory pathways in an AD-relevant genotype and that soluble TNF has sex-dependent roles in modulating these pathways across anatomical compartments. Modulation of energy homeostasis and inflammation may provide new therapeutic avenues for AD.

Alzheimer's disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner.

Genome-wide association studies have identified a protective mutation in the phospholipase C gamma 2 (PLCG2) gene which confers protection against Alzheimer's disease (AD)-associated cognitive decline. Therefore, PLCG2, which is primarily expressed in immune cells, has become a target of interest for potential therapeutic intervention. The protective allele, known as P522R, has been shown to be hyper-morphic in microglia, increasing phagocytosis of amyloid-beta (Aß), and increasing the release of inflammatory cytokines. However, the effect of this protective mutation on peripheral tissue-resident macrophages, and the extent to which sex modifies this effect, has yet to be assessed. Herein, we show that peripheral macrophages carrying the P522R mutation do indeed show functional differences compared to their wild-type (WT) counterparts, however, these alterations occur in a sex-dependent manner. In macrophages from females, the P522R mutation increases lysosomal protease activity, cytokine secretion, and gene expression associated with cytokine secretion and apoptosis. In contrast, in macrophages from males, the mutation causes decreased phagocytosis and lysosomal protease activity, modest increases in cytokine secretion, and induction of gene expression associated with negative regulation of the immune response. Taken together, these results suggest that the mutation may be conferring different effects dependent on sex and cell type, and highlight the importance of considering sex as a biological variable when assessing the effects of genetic variants and implications for potential immune system-targeted therapies.

Modulation of cannabinoid receptor 2 alters neuroinflammation and reduces formation of alpha-synuclein aggregates in a rat model of nigral synucleinopathy.

Research into the disequilibrium of microglial phenotypes has become an area of intense focus in neurodegenerative disease as a potential mechanism that contributes to chronic neuroinflammation and neuronal loss in Parkinson's disease (PD). There is growing evidence that neuroinflammation accompanies and may promote progression of alpha-synuclein (Asyn)-induced nigral dopaminergic (DA) degeneration. From a therapeutic perspective, development of immunomodulatory strategies that dampen overproduction of pro-inflammatory cytokines from chronically activated immune cells and induce a pro-phagocytic phenotype is expected to promote Asyn removal and protect vulnerable neurons. Cannabinoid receptor-2 (CB2) is highly expressed on activated microglia and peripheral immune cells, is upregulated in the substantia nigra of individuals with PD and in mouse models of nigral degeneration. Furthermore, modulation of CB2 protects against rotenone-induced nigral degeneration; however, CB2 has not been pharmacologically and selectively targeted in an Asyn model of PD. Here, we report that 7 weeks of peripheral administration of CB2 inverse agonist SMM-189 reduced phosphorylated (pSer129) Asyn in the substantia nigra compared to vehicle treatment. Additionally, SMM-189 delayed Asyn-induced immune cell infiltration into the brain as determined by flow cytometry, increased CD68 protein expression, and elevated wound-healing-immune-mediator gene expression. Additionally, peripheral immune cells increased wound-healing non-classical monocytes and decreased pro-inflammatory classical monocytes. In vitro analysis of RAW264.7 macrophages treated with lipopolysaccharide (LPS) and SMM-189 revealed increased phagocytosis as measured by the uptake of fluorescence of pHrodo E. coli bioparticles. Together, results suggest that targeting CB2 with SMM-189 skews immune cell function toward a phagocytic phenotype and reduces toxic aggregated species of Asyn. Our novel findings demonstrate that CB2 may be a target to modulate inflammatory and immune responses in proteinopathies.

A leaky gut dysregulates gene networks in the brain associated with immune activation, oxidative stress, and myelination in a mouse model of colitis.

The gut and brain are increasingly linked in human disease, with neuropsychiatric conditions classically attributed to the brain showing an involvement of the intestine and inflammatory bowel diseases (IBDs) displaying an ever-expanding list of neurological comorbidities. To identify molecular systems that underpin this gut-brain connection and thus discover therapeutic targets, experimental models of gut dysfunction must be evaluated for brain effects. In the present study, we examine disturbances along the gut-brain axis in a widely used murine model of colitis, the dextran sodium sulfate (DSS) model, using high-throughput transcriptomics and an unbiased network analysis strategy coupled with standard biochemical outcome measures to achieve a comprehensive approach to identify key disease processes in both colon and brain. We examine the reproducibility of colitis induction with this model and its resulting genetic programs during different phases of disease, finding that DSS-induced colitis is largely reproducible with a few site-specific molecular features. We focus on the circulating immune system as the intermediary between the gut and brain, which exhibits an activation of pro-inflammatory innate immunity during colitis. Our unbiased transcriptomics analysis provides supporting evidence for immune activation in the brain during colitis, suggests that myelination may be a process vulnerable to increased intestinal permeability, and identifies a possible role for oxidative stress and brain oxygenation. Overall, we provide a comprehensive evaluation of multiple systems in a prevalent experimental model of intestinal permeability, which will inform future studies using this model and others, assist in the identification of druggable targets in the gut-brain axis, and contribute to our understanding of the concomitance of intestinal and neuropsychiatric dysfunction.

Biochemical Fractionation of Human α-Synuclein in a Drosophila Model of Synucleinopathies.

Synucleinopathies are a group of central nervous system pathologies that are characterized by the intracellular accumulation of misfolded and aggregated α-synuclein in proteinaceous depositions known as Lewy Bodies (LBs). The transition of α-synuclein from its physiological to pathological form has been associated with several post-translational modifications such as phosphorylation and an increasing degree of insolubility, which also correlate with disease progression in post-mortem specimens from human patients. Neuronal expression of α-synuclein in model organisms, including Drosophila melanogaster, has been a typical approach employed to study its physiological effects. Biochemical analysis of α-synuclein solubility via high-speed ultracentrifugation with buffers of increasing detergent strength offers a potent method for identification of α-synuclein biochemical properties and the associated pathology stage. Unfortunately, the development of a robust and reproducible method for the evaluation of human α-synuclein solubility isolated from Drosophila tissues has remained elusive. Here, we tested different detergents for their ability to solubilize human α-synuclein carrying the pathological mutation A53T from the brains of aged flies. We also assessed the effect of sonication on the solubility of human α-synuclein and optimized a protocol to discriminate the relative amounts of soluble/insoluble human α-synuclein from dopaminergic neurons of the Drosophila brain. Our data established that, using a 5% SDS buffer, the three-step protocol separates cytosolic soluble, detergent-soluble and insoluble proteins in three sequential fractions according to their chemical properties. This protocol shows that sonication breaks down α-synuclein insoluble complexes from the fly brain, making them soluble in the SDS buffer and thus enriching the detergent-soluble fraction of the protocol.

The complex role of inflammation and gliotransmitters in Parkinson's disease.

Our understanding of the role of innate and adaptive immune cell function in brain health and how it goes awry during aging and neurodegenerative diseases is still in its infancy. Inflammation and immunological dysfunction are common components of Parkinson's disease (PD), both in terms of motor and non-motor components of PD. In recent decades, the antiquated notion that the central nervous system (CNS) in disease states is an immune-privileged organ, has been debunked. The immune landscape in the CNS influences peripheral systems, and peripheral immunological changes can alter the CNS in health and disease. Identifying immune and inflammatory pathways that compromise neuronal health and survival is critical in designing innovative and effective strategies to limit their untoward effects on neuronal health.

Progranulin and GPNMB: interactions in endo-lysosome function and inflammation in neurodegenerative disease.

BACKGROUND: Alterations in progranulin (PGRN) expression are associated with multiple neurodegenerative diseases (NDs), including frontotemporal dementia (FTD), Alzheimer's disease (AD), Parkinson's disease (PD), and lysosomal storage disorders (LSDs). Recently, the loss of PGRN was shown to result in endo-lysosomal system dysfunction and an age-dependent increase in the expression of another protein associated with NDs, glycoprotein non-metastatic B (GPNMB). MAIN BODY: It is unclear what role GPNMB plays in the context of PGRN insufficiency and how they interact and contribute to the development or progression of NDs. This review focuses on the interplay between these two critical proteins within the context of endo-lysosomal health, immune function, and inflammation in their contribution to NDs. SHORT CONCLUSION: PGRN and GPNMB are interrelated proteins that regulate disease-relevant processes and may have value as therapeutic targets to delay disease progression or extend therapeutic windows.

APOE and immunity: Research highlights.

INTRODUCTION: At the Alzheimer's Association's APOE and Immunity virtual conference, held in October 2021, leading neuroscience experts shared recent research advances on and inspiring insights into the various roles that both the apolipoprotein E gene (APOE) and facets of immunity play in neurodegenerative diseases, including Alzheimer's disease and other dementias. METHODS: The meeting brought together more than 1200 registered attendees from 62 different countries, representing the realms of academia and industry. RESULTS: During the 4-day meeting, presenters illuminated aspects of the cross-talk between APOE and immunity, with a focus on the roles of microglia, triggering receptor expressed on myeloid cells 2 (TREM2), and components of inflammation (e.g., tumor necrosis factor α [TNFα]). DISCUSSION: This manuscript emphasizes the importance of diversity in current and future research and presents an integrated view of innate immune functions in Alzheimer's disease as well as related promising directions in drug development.

Addressing the disparities in dementia risk, early detection and care in Latino populations: Highlights from the second Latinos & Alzheimer's Symposium.

The Alzheimer's Association hosted the second Latinos & Alzheimer's Symposium in May 2021. Due to the COVID-19 pandemic, the meeting was held online over 2 days, with virtual presentations, discussions, mentoring sessions, and posters. The Latino population in the United States is projected to have the steepest increase in Alzheimer's disease (AD) in the next 40 years, compared to other ethnic groups. Latinos have increased risk for AD and other dementias, limited access to quality care, and are severely underrepresented in AD and dementia research and clinical trials. The symposium highlighted developments in AD research with Latino populations, including advances in AD biomarkers, and novel cognitive assessments for Spanish-speaking populations, as well as the need to effectively recruit and retain Latinos in clinical research, and how best to deliver health-care services and to aid caregivers of Latinos living with AD.

Transgenic Mice Expressing Human α-Synuclein in Noradrenergic Neurons Develop Locus Ceruleus Pathology and Nonmotor Features of Parkinson's Disease.

Degeneration of locus ceruleus (LC) neurons and dysregulation of noradrenergic signaling are ubiquitous features of Parkinson's disease (PD). The LC is among the first brain regions affected by α-synuclein (asyn) pathology, yet how asyn affects these neurons remains unclear. LC-derived norepinephrine (NE) can stimulate neuroprotective mechanisms and modulate immune cells, while dysregulation of NE neurotransmission may exacerbate disease progression, particularly nonmotor symptoms, and contribute to the chronic neuroinflammation associated with PD pathology. Although transgenic mice overexpressing asyn have previously been developed, transgene expression is usually driven by pan-neuronal promoters and thus has not been selectively targeted to LC neurons. Here we report a novel transgenic mouse expressing human wild-type asyn under control of the noradrenergic-specific dopamine ß-hydroxylase promoter (DBH-hSNCA). These mice developed oligomeric and conformation-specific asyn in LC neurons, alterations in hippocampal and LC microglial abundance, upregulated GFAP expression, degeneration of LC fibers, decreased striatal DA metabolism, and age-dependent behaviors reminiscent of nonmotor symptoms of PD that were rescued by adrenergic receptor antagonists. These mice provide novel insights into how asyn pathology affects LC neurons and how central noradrenergic dysfunction may contribute to early PD pathophysiology.SIGNIFICANCE STATEMENT ɑ-Synuclein (asyn) pathology and loss of neurons in the locus ceruleus (LC) are two of the most ubiquitous neuropathologic features of Parkinson's disease (PD). Dysregulated norepinephrine (NE) neurotransmission is associated with the nonmotor symptoms of PD, including sleep disturbances, emotional changes such as anxiety and depression, and cognitive decline. Importantly, the loss of central NE may contribute to the chronic inflammation in, and progression of, PD. We have generated a novel transgenic mouse expressing human asyn in LC neurons to investigate how increased asyn expression affects the function of the central noradrenergic transmission and associated behaviors. We report cytotoxic effects of oligomeric and conformation-specific asyn, astrogliosis, LC fiber degeneration, disruptions in striatal dopamine metabolism, and age-dependent alterations in nonmotor behaviors without inclusions.

Peripheral endotoxin exposure in mice activates crosstalk between phagocytes in the brain and periphery.

Background: Inflammation is a central process of many neurological diseases, and a growing number of studies suggest that non-brain-resident immune cells may contribute to this neuroinflammation. However, the unique contributions of specific immune cell subsets to neuroinflammation are presently unknown, and it is unclear how communication between brain-resident and non-resident immune cells underlies peripheral immune cell involvement in neuroinflammation. Methods: In this study, we employed the well-established model of lipopolysaccharide (LPS)-induced neuroinflammation and captured brain-resident and non-resident immune cells from the brain and its vasculature by magnetically enriching cell suspensions from the non-perfused brain for CD45 + cells. Then, we identified immune subtype-specific neuroinflammatory processes using single-cell genomics and predicted the crosstalk between immune cell subtypes by analyzing the simultaneous expression of ligands and receptors. Results: We observed a greater abundance of peripheral phagocytes associated with the brain in this model of neuroinflammation, and report that these professional phagocytes activated similar transcriptional profiles to microglia during LPS-induced neuroinflammation. And, we observed that the probable crosstalk between microglia and peripheral phagocytes was activated in this model while homotypic microglial communication was likely to be decreased. Conclusions: Our novel findings reveal that microglia signaling to non-brain-resident peripheral phagocytes is preferentially triggered by peripheral inflammation, which is associated with brain infiltration of peripheral cells. Overall, our study supports the involvement of peripheral immune cells in neuroinflammation and suggests several possible molecular signaling pathways between microglia and peripheral cells that may facilitate central-peripheral crosstalk during inflammation. Examining these molecular mediators in human disease and other rodent models may reveal novel targets that modify brain health, especially in comorbidities characterized by peripheral inflammation.

Thinking outside the brain: Gut microbiome influence on innate immunity within neurodegenerative disease.

The complex network of factors that contribute to neurodegeneration have hampered the discovery of effective preventative measures. While much work has focused on brain-first therapeutics, it is becoming evident that physiological changes outside of the brain are the best target for early interventions. Specifically, myeloid cells, including peripheral macrophages and microglia, are a sensitive population of cells whose activity can directly impact neuronal health. Myeloid cell activity includes cytokine production, migration, debris clearance, and phagocytosis. Environmental measures that can modulate these activities range from toxin exposure to diet. However, one of the most influential mediators of myeloid fitness is the gut microenvironment. Here, we review the current data about the role of myeloid cells in gastrointestinal disorders, Parkinson's disease, dementia, and multiple sclerosis. We then delve into the gut microbiota modulating therapies available and clinical evidence for their use in neurodegeneration. Modulating lifestyle and environmental mediators of inflammation are one of the most promising interventions for neurodegeneration and a systematic and concerted effort to examine these factors in healthy aging is the next frontier.

Investigating the Role and Regulation of GPNMB in Progranulin-deficient Macrophages.

Progranulin is a holoprotein that is critical for successful aging, and insufficient levels of progranulin are associated with increased risk for developing age-related neurodegenerative diseases like AD, PD, and FTD. Symptoms can vary widely, but a uniting feature among these different neurodegenerative diseases is prodromal peripheral immune cell phenotypes. However, there remains considerable gaps in the understanding of the function(s) of progranulin in immune cells, and recent work has identified a novel target candidate called GPNMB. We addressed this gap by investigating the peritoneal macrophages of 5-6-month-old Grn KO mice, and we discovered that GPNMB is actively increased as a result of insufficient progranulin and that MITF, a transcription factor, is also dysregulated in progranulin-deficient macrophages. These findings highlight the importance of early-stage disease mechanism(s) in peripheral cell populations that may lead to viable treatment strategies to delay disease progression at an early, prodromal timepoint and extend therapeutic windows.

Biochemical fractionation of human α-Synuclein in a Drosophila model of synucleinopathies.

Synucleinopathies are a group of central nervous system pathologies that are characterized by neuronal accumulation of misfolded and aggregated α-synuclein in proteinaceous depositions known as Lewy Bodies (LBs). The transition of α-synuclein from its physiological to pathological form has been associated with several post-translational modifications such as phosphorylation and an increasing degree of insolubility, which also correlate with disease progression in postmortem specimens from human patients. Neuronal expression of α-synuclein in model organisms, including Drosophila melanogaster, has been a typical approach employed to study its physiological effects. Biochemical analysis of α-synuclein solubility via high-speed ultracentrifugation with buffers of increasing detergent strength offers a potent method for identification of α-synuclein biochemical properties and the associated pathology stage. Unfortunately, the development of a robust and reproducible method for evaluation of human α-synuclein solubility isolated from Drosophila tissues has remained elusive. Here, we tested different detergents for their ability to solubilize human α-synuclein carrying the pathological mutation A53T from brains of aged flies. We also assessed the effect of sonication on solubility of human α-synuclein and optimized a protocol to discriminate relative amounts of soluble/insoluble human α-synuclein from dopaminergic neurons of the Drosophila brain. Our data established that, using a 5% SDS buffer, the 3-step protocol distinguishes between cytosolic soluble proteins in fraction 1, detergent-soluble proteins in fraction 2 and insoluble proteins in fraction 3. This protocol shows that sonication breaks down α-synuclein insoluble complexes from the fly brain, making them soluble in the SDS buffer and enriching fraction 2 of the protocol.

Locus coeruleus injury modulates ventral midbrain neuroinflammation during DSS-induced colitis.

Parkinson's disease (PD) is characterized by a decades-long prodrome, consisting of a collection of non-motor symptoms that emerges prior to the motor manifestation of the disease. Of these non-motor symptoms, gastrointestinal dysfunction and deficits attributed to central norepinephrine (NE) loss, including mood changes and sleep disturbances, are frequent in the PD population and emerge early in the disease. Evidence is mounting that injury and inflammation in the gut and locus coeruleus (LC), respectively, underlie these symptoms, and the injury of these systems is central to the progression of PD. In this study, we generate a novel two-hit mouse model that captures both features, using dextran sulfate sodium (DSS) to induce gut inflammation and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) to lesion the LC. We first confirmed the specificity of DSP-4 for central NE using neurochemical methods and fluorescence light-sheet microscopy of cleared tissue, and established that DSS-induced outcomes in the periphery, including weight loss, gross indices of gut injury and systemic inflammation, the loss of tight junction proteins in the colonic epithelium, and markers of colonic inflammation, were unaffected with DSP-4 pre-administration. We then measured alterations in neuroimmune gene expression in the ventral midbrain in response to DSS treatment alone as well as the extent to which prior LC injury modified this response. In this two-hit model we observed that DSS-induced colitis activates the expression of key cytokines and chemokines in the ventral midbrain only in the presence of LC injury and the typical DSS-associated neuroimmune is blunted by pre-LC lesioning with DSP-4. In all, this study supports the growing appreciation for the LC as neuroprotective against inflammation-induced brain injury and draws attention to the potential for NEergic interventions to exert disease-modifying effects under conditions where peripheral inflammation may compromise ventral midbrain dopaminergic neurons and increase the risk for development of PD.

Investigating the role and regulation of GPNMB in progranulin-deficient macrophages.

Introduction: Progranulin (PGRN) is a holoprotein that is internalized and taken to the lysosome where it is processed to individual granulins (GRNs). PGRN is critical for successful aging, and insufficient levels of PGRN are associated with increased risk for developing neurodegenerative diseases like AD, PD, and FTD. A unifying feature among these diseases is dysregulation of peripheral immune cell populations. However, considerable gaps exist in our understanding of the function(s) of PGRN/GRNs in immune cells and their role in regulating central-peripheral neuroimmune crosstalk. One of the most upregulated genes and proteins in humans with GRN haploinsufficiency and in aged Grn knock-out (KO) mice is glycoprotein non-metastatic B (GPNMB) but its normal role within the context of immune crosstalk has not been elucidated. Methods: To address this gap, peritoneal macrophages (pMacs) from 5-to-6-month old WT and Grn KO mice were assessed for Gpnmb expression and stimulation-dependent cytokine release in the presence or absence of the Gpnmb extracellular domain (ECD). Cellular localization, as well as inhibition of, the microphthalmia-associated transcription factor (MITF) was assessed to determine its mechanistic role in Gpnmb overexpression in Grn KO pMacs. Results: We observed an increase in GPNMB protein and mRNA as a result of insufficient progranulin in peripheral immune cells at a very early age relative to previous reports on the brain. Stimulation-dependent cytokine release was decreased in the media of Grn KO pMacs relative to WT controls; a phenotype that could be mimicked in WT pMacs with the addition og GPNMB ECD. We also found that MITF is dysregulated in Grn KO pMacs; however, its nuclear translocation and activity are not required to rescue the immune dysregulation of Grn KO macrophages, suggesting redundancy in the system. Discussion: These findings highlight the fact that knowledge of early-stage disease mechanism(s) in peripheral populations may inform treatment strategies to delay disease progression at an early, prodromal timepoint prior to development of neuroinflammation and CNS pathology.

Peripheral Blood Immune Cells from Individuals with Parkinson's Disease or Inflammatory Bowel Disease Share Deficits in Iron Storage and Transport that are Modulated by Non-Steroidal Anti-Inflammatory Drugs.

Parkinson's Disease (PD) is a multisystem disorder in which dysregulated neuroimmune crosstalk and inflammatory relay via the gut-blood-brain axis have been implicated in PD pathogenesis. Although alterations in circulating inflammatory cytokines and reactive oxygen species (ROS) have been associated with PD, no biomarkers have been identified that predict clinical progression or disease outcome. Gastrointestinal (GI) dysfunction, which involves perturbation of the underlying immune system, is an early and often-overlooked symptom that affects up to 80% of individuals living with PD. Interestingly, 50-70% of individuals with inflammatory bowel disease (IBD), a GI condition that has been epidemiologically linked to PD, display chronic illness-induced anemia - which drives toxic accumulation of iron in the gut. Ferroptotic (or iron loaded) cells have small and dysmorphic mitochondria-suggesting that mitochondrial dysfunction is a consequence of iron accumulation. In pro-inflammatory environments, iron accumulates in immune cells, suggesting a possible connection and/or synergy between iron dysregulation and immune cell dysfunction. Peripheral blood mononuclear cells (PBMCs) recapitulate certain PD-associated neuropathological and inflammatory signatures and can act as communicating messengers in the gut-brain axis. Additionally, this communication can be modulated by several environmental factors; specifically, our data further support existing literature demonstrating a role for non-steroidal anti-inflammatory drugs (NSAIDs) in modulating immune transcriptional states in inflamed individuals. A mechanism linking chronic gut inflammation to iron dysregulation and mitochondrial function within peripheral immune cells has yet to be identified in conferring risk for PD. To that end, we isolated PBMCs and simultaneously evaluated their directed transcriptome and bioenergetic status, to investigate if iron dysregulation and mitochondrial sensitization are linked in individuals living with PD or IBD because of chronic underlying remittent immune activation. We have identified shared features of peripheral inflammation and immunometabolism in individuals living with IBD or PD that may contribute to the epidemiological association reported between IBD and risk for PD.

Diet-induced metabolic and immune impairments are sex-specifically modulated by soluble TNF signaling in the 5xFAD mouse model of Alzheimer's disease.

Emerging evidence indicates that high-fat, high carbohydrate diet (HFHC) impacts central pathological features of Alzheimer's disease (AD) across both human incidences and animal models. However, the mechanisms underlying this association are poorly understood. Here, we identify compartment-specific metabolic and inflammatory dysregulations that are induced by HFHC diet in the 5xFAD mouse model of AD pathology. We observe that both male and female 5xFAD mice display exacerbated adiposity, cholesterolemia, and dysregulated insulin signaling. Independent of biological sex, HFHC diet also resulted in altered inflammatory cytokine profiles across the gastrointestinal, circulating, and central nervous systems (CNS) compartments demonstrating region-specific impacts of metabolic inflammation. In male mice, we note that HFHC triggered increases in amyloid beta, an observation not seen in female mice. Interestingly, inhibiting the inflammatory cytokine, soluble tumor necrosis factor (TNF) with the brain-permeant soluble TNF inhibitor XPro1595 was able to restore aspects of HFHC-induced metabolic inflammation, but only in male mice. Targeted transcriptomics of CNS regions revealed that inhibition of soluble TNF was sufficient to alter expression of hippocampal and cortical genes associated with beneficial immune and metabolic responses. Collectively, these results suggest that HFHC diet impairs metabolic and inflammatory pathways in an AD-relevant genotype and that soluble TNF has sex-dependent roles in modulating these pathways across anatomical compartments. Modulation of energy homeostasis and inflammation may provide new therapeutic avenues for AD.