IL-34 exacerbates pathogenic features of Alzheimer's disease and calvaria osteolysis in triple transgenic (3x-Tg) female mice.

Hallmark features of Alzheimer's disease (AD) include elevated accumulation of aggregated Aß40 and Aß42 peptides, hyperphosphorylated Tau (p-Tau), and neuroinflammation. Emerging evidence indicated that interleukin-34 (IL-34) contributes to AD and inflammatory osteolysis via the colony-stimulating factor-1 receptor (CSF-1r). In addition, CSF-1r is also activated by macrophage colony-stimulating factor-1 (M-CSF). While the role of M-CSF in bone physiology and pathology is well addressed, it remains controversial whether IL-34-mediated signaling promotes osteolysis, neurodegeneration, and neuroinflammation in relation to AD. In this study, we injected 3x-Tg mice with mouse recombinant IL-34 protein over the calvaria bone every other day for 42 days. Then, behavioral changes, brain pathology, and calvaria osteolysis were evaluated using various behavioral maze and histological assays. We demonstrated that IL-34 administration dramatically elevated AD-like anxiety and memory loss, pathogenic amyloidogenesis, p-Tau, and RAGE expression in female 3x-Tg mice. Furthermore, IL-34 delivery promoted calvaria inflammatory osteolysis compared to the control group. In addition, we also compared the effects of IL-34 and M-CSF on macrophages, microglia, and RANKL-mediated osteoclastogenesis in relation to AD pathology in vitro. We observed that IL-34-exposed SIM-A9 microglia and 3x-Tg bone marrow-derived macrophages released significantly elevated amounts of pro-inflammatory cytokines, TNF-α, IL-1ß, and IL-6, compared to M-CSF treatment in vitro. Furthermore, IL-34, but not M-CSF, elevated RANKL-primed osteoclastogenesis in the presence of Aß40 and Aß42 peptides in bone marrow derived macrophages isolated from female 3x-Tg mice. Collectively, our data indicated that IL-34 elevates AD-like features, including behavioral changes and neuroinflammation, as well as osteoclastogenesis in female 3x-Tg mice.

The dissociation of temporal processing behavior in concussion patients: Stable motor and dynamic perceptual timing.

Temporal processing is an integral aspect of human cognition and perception. Recent studies have suggested that patients suffering from concussion exhibit a deficit in temporal processing, characterized by poor performance on a variety of timing tasks. However, the majority of studies focusing on temporal processing deficits in concussion have focused on visual timing mechanisms. As temporal processing may be dominant for auditory-based processing, and so less susceptible to noise, we investigated patients with TBI and compared them to normal healthy controls on a battery of temporal processing tasks, including paced finger tapping and temporal bisection with sub-second intervals. The results of our investigation found that traumatic brain patients were unimpaired on the paced finger tapping task, suggesting that temporal processing deficits do not extend into motor timing and rhythmicity domain. In the temporal bisection task, TBI patients maintained precision but had a significantly higher bisection point, characterized by a greater propensity to judge stimuli as "short" and were significantly slower than controls. Analysis with a drift-diffusion model of perceptual decision-making revealed that TBI patients were specifically impaired in evidence accumulation, suggesting a smaller signal to noise ratio. Specifically, it demonstrated that patients had higher decision threshold and slower drift rates for accumulating evidence in order to arrive at a decision. Patients had to surmount higher evidence thresholds to reach a decision and were slower than controls in their rate of evidence accumulation. These results suggest specific deficits in temporal perceptual decision-making may predict the neural temporal pathways that may be compromised or unaffected, paving the way for designing targeted therapies to address these impairments.

Zinc Exacerbates Tau Pathology in a Tau Mouse Model.

Hyperphosphorylated tau protein is a key pathology in Alzheimer's disease (AD), frontotemporal dementia, chronic traumatic encephalopathy, and Parkinson's disease. The essential trace element zinc exacerbates tauopathy in vitro as well as in a Drosophila model of AD. However, the interaction has never been assessed behaviorally or biochemically in mammals. Zinc supplementation is prevalent in society, finding use as a treatment for macular degeneration and cataracts, and is also taken as an immune system booster with high levels appearing in multivitamins marketed toward the elderly. Using a transgenic mouse model that contains the human gene for tau protein (P301L), we assessed the effects of excess chronic zinc supplementation on tau pathology. Behavioral tests included nest building, circadian rhythm, Morris Water Maze, fear conditioning, and open field. Biochemically, total tau and Ser396 phosphorylation were assessed using western blot. Number of tangles were assessed by Thioflavin-S and free zinc levels were assessed by Zinpyr-1. Tau mice demonstrated behavioral deficits compared to control mice. Zinc supplementation exacerbated tauopathic deficits in circadian rhythm, nesting behavior, and Morris Water Maze. Biochemically, zinc-supplemented tau mice showed increased phosphorylation at pSer396. Zinc supplementation in tau mice also increased tangle numbers in the hippocampus while decreasing free-zinc levels, demonstrating that tangles were sequestering zinc. These results show that zinc intensified the deficits in behavior and biochemistry caused by tau.