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.

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.

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.

BackgroundAlzheimer’s disease (AD) is a multifactorial disorder associated with the accumulation of soluble forms of beta-amyloid (Aβ) and its subsequent deposition into plaques. One of the major contributors to neuronal death is chronic and uncontrolled inflammatory activation of microglial cells around the plaques and their secretion of neurotoxic molecules. A shift in microglial activation towards a phagocytic phenotype has been proposed to confer benefit in models of AD. Peroxisome proliferator activator receptor δ (PPARδ) is a transcription factor with potent anti-inflammatory activation properties and PPARδ agonism leads to reduction in brain Aβ levels in 5XFAD mice. This study was carried out to elucidate the involvement of microglial activation in the PPARδ-mediated reduction of Aβ burden and subsequent outcome to neuronal survival in a 5XFAD mouse model of AD.Methods5XFAD mice were orally treated with the PPARδ agonist GW0742 for 2 weeks. The brain Aβ load, glial activation, and neuronal survival were assessed by immunohistochemistry and quantitative PCR. In addition, the ability of GW0742 to prevent direct neuronal death as well as inflammation-induced neuron death was analyzed in vitro.ResultsOur results show for the first time that a short treatment period of 5XFAD mice was effective in reducing the parenchymal Aβ load without affecting the levels of intraneuronal Aβ. This was concomitant with a decrease in overall microglial activation and reduction in proinflammatory mediators. Instead, microglial immunoreactivity around Aβ deposits was increased. Importantly, the reduction in the proinflammatory milieu elicited by GW0742 treatment resulted in attenuation of neuronal loss in vivo in the subiculum of 5XFAD mice. In addition, whereas GW0742 failed to protect primary neurons against glutamate-induced cell death, it prevented inflammation-induced neuronal death in microglia-neuron co-cultures in vitro.ConclusionsThis study demonstrates that GW0742 treatment has a prominent anti-inflammatory effect in 5XFAD mice and suggests that PPARδ agonists may have therapeutic utility in treating AD.

Nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor which plays a critical role in maintenance of cellular redox, has been identified as a therapeutic target in a number of human diseases. Several reports have demonstrated beneficial effects of NRF2 manipulation in animal models of disease, and one NRF2-activating drug, dimethyl fumarate, is already approved for the treatment of multiple sclerosis. However, drug discovery is slowed due to a dearth of biomarkers which can inform target engagement and magnitude and duration of action. Peripheral blood mononuclear cells (PBMCs) are an accessible, minimally-invasive source of biomarkers which can be readily assayed and objectively monitored as a surrogate endpoint of NRF2 activation in clinical trials. We undertook a review of the literature on PBMC NRF2 measurements in human studies to explore its role as a suitable biomarker in various contexts of health and disease. It is clear that NRF2 and its target genes can be readily assayed from PBMCs in multiple disease contexts and may track with disease progression. Further work needs to be undertaken to evaluate its stability but should be considered as an exploratory marker in clinical trials targeting NRF2 activation.

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While conventional magnetic resonance imaging (MRI) is central to the evaluation of patients with multiple sclerosis, its role in detecting the pathophysiology underlying neurodegeneration is more limited. One of the common outcome measures for progressive multiple sclerosis trials, atrophy on brain MRI, is non-specific and reflects end-stage changes after considerable neurodegeneration has occurred. Identifying biomarkers that identify processes underlying neurodegeneration before it is irreversible and that reflect relevant neurodegenerative pathophysiology is an area of significant need. Accumulating evidence suggests that oxidative stress plays a major role in the pathogenesis of multiple neurodegenerative diseases, including multiple sclerosis. Imaging markers related to inflammation, myelination, and neuronal integrity have been areas of advancement in recent years but oxidative stress has remained an area of unrealized potential. In this article we will begin by reviewing the role of oxidative stress in the pathogenesis of multiple sclerosis. Chronic inflammation appears to be directly related to the increased production of reactive oxygen species and the effects of subsequent oxidative stress appear to be amplified by aging and accumulating disease. We will then discuss techniques in development used in the assessment of MS as well as other models of neurodegenerative disease in which oxidative stress is implicated. Multiple blood and CSF markers of oxidative stress have been evaluated in subjects with MS, but non-invasive imaging offers major upside in that it provides real-time assessment within the brain.

Neuroinflammation has long been associated with many neurodegenerative diseases (NDDs). Immune-related genetic and environmental risk factors have recently been identified for NDDs, suggesting that neuroinflammation can play an active role in modifying NDD pathologies. Immune cells that underlie this neuroinflammatory response can have both beneficial and detrimental roles in NDDs. These cells can engage in clearance of debris and provide important survival factors to neighboring neurons. However, these cells can also release inflammatory molecules that promote oxidative stress and excitotoxic damage in surrounding neurons, and aberrantly clear healthy cells and structures from the brain. In turn, the cells within the brain play important roles in determining the phenotype and function of these immune cells, and changes in the interaction among these cells in the context of disease can lead to detrimental immune cell activation. There has been recent interest in developing inflammation-related biomarkers to help diagnose NDDs and immune-targeted therapeutics.