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.

Alzheimer’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. 5XFAD 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. Our 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. This 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.

Thermoregulatory dysfunction—temperature intolerance and/or inappropriate compensation—is an underrecognized feature of Parkinson’s disease (PD) and is linked to poor quality of life. Multiple mechanisms may underlie this dysfunction, including α-synuclein deposition in relevant structures, altered functional connectivity in thermoregulatory networks, and disrupted neurotransmitter modulation, on top of the deleterious consequences of aging. Although multiple advanced tests can confirm this dysfunction, diagnosis is largely based on a detailed history. Once this critical symptom is identified, management focuses on crisis prevention and safety, as PD-specific clinical trials are often lacking. This narrative review of the literature addresses mechanisms, clinical expression, diagnostic evaluation, and management of thermoregulatory dysfunction in PD to help guide care for this underappreciated, yet potentially debilitating, non-motor symptom of PD. Future PD-specific trials are needed to further clarify underlying mechanisms and improve treatment options.