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Alzheimer's disease is marked by the presence of amyloid-beta (Aβ) plaques, elevated central cytokine levels, dysregulation of BDNF-related gene expression, and cognitive decline. Previously, our laboratory has demonstrated that repeated administration of peripheral LPS is sufficient to significantly increase the presence of central Aβ in the hippocampus, and that this upregulation corresponds with deficits in learning and memory. We have also previously demonstrated that the inverse benzodiazepine agonist MRK-016 (MRK) can protect against memory acquisition and consolidation errors in mice. To extend these findings, the current study explored the protective effects of MRK in the context of LPS-induced hippocampal Aβ accumulation. Hippocampal Aβ was significantly elevated, relative to saline-treated animals, following seven days of peripheral LPS injections. Animals were then trained in a contextual fear conditioning paradigm and were immediately treated with MRK or saline once training was complete. Behavioral testing occurred the day after training. Results from this study demonstrate that repeated injections of LPS significantly elevate hippocampal Aβ, and inhibit acquisition of contextual fear. Post-training treatment with MRK restored behavioral expression of fear in LPS-treated animals, despite elevated hippocampal Aβ, an effect that may be attributed to increased BDNF mRNA expression. Therefore, our data indicate that MRK can prevent LPS- induced cognitive deficits associated with elevated Aβ, and restore hippocampal BDNF expression.

Although one of the defining characteristics of Alzheimer’s disease is the presence of amyloid-beta (Aβ) plaques, the early accumulation of soluble Aβ oligomers (AβOs) may disrupt synaptic function and trigger cognitive impairments long before the appearance of plaques. Furthermore, murine models aimed at understanding how AβOs alter formation and retrieval of associative memories are conducted using human Aβ species, which are more neurotoxic in the mouse brain than the native murine species. Unfortunately, there is currently a lack of attention in the literature as to what the murine version of the peptide (mAβ) does to synaptic function and how it impacts the consolidation and retrieval of associative memories. In the current study, adult mice were infused with mAβ 0, 2, 6, or 46 h after contextual-fear conditioning, and were tested 2–48 h later. Interestingly, only mAβ infusions within 2 h of training reduced freezing behavior at test, indicating that mAβ disrupted the consolidation, but not retrieval of fear memory. This consolidation deficit coincided with increased IL-1β and reduced synaptophysin mRNA levels, without disrupting other synaptic signaling-related genes here examined. Despite differences between murine and human Aβ, the deleterious functional outcomes of early-stage synaptic oligomer presence are similar. Thus, models utilizing or inducing the production of mAβ in non-transgenic animals are useful in exploring the role of dysregulated synaptic plasticity and resultant learning deficits induced by Aβ oligomers.

Alzheimer's disease is marked by the accumulation of the amyloid-beta (Aβ) peptide, and increases in phosphorylation of the microtubule associated protein, tau. Changes in these proteins are considered responsible, in part, for the progressive neuronal degeneration and cognitive deficits seen in AD. We examined the effect of repeated consecutive peripheral poly I:C injections on cognitive deficits, central Aβ, and phosphorylated tau accumulation, following three treatment durations: 7, 14, and 21 days. Forty-eight hours after the final injection, animals were trained in a contextual fear-conditioning paradigm, and tested 24h later. Immediately after testing, the hippocampus was collected to quantify Aβ and phosphorylated tau accumulation. Results showed that, although poly I:C-induced Aβ was significantly elevated at all time points examined, poly I:C only disrupted cognition after 14 and 21 days of administration. Moreover, elevations in phosphorylated tau were not seen until the 14-day time point. Interestingly, phosphorylated tau expression then declined at the 21-day time point. Finally, we demonstrated that Aβ levels are a stronger predictor of cognitive dysfunction, explaining 37% of the variance, whereas phosphorylated tau levels only accounted for 0.2%. Taken together, these results support the hypothesis that inflammation-induced elevation in Aβ disrupts cognition, independently of phosphorylated tau, and suggest that long-term administration of poly I:C may provide a model to investigate the contribution of long-term inflammation toward the development of Alzheimer's-like pathology.

Research has demonstrated that stress can exacerbate AD pathology in transgenic mouse models of AD. The purpose of the present studies was to extend this work by determining whether a social stressor, isolation stress, would increase the number of Aβ plaques in 5xFAD + transgenic mice in comparison to group-housed controls, and accelerate the onset of cognitive deficits in contextual fear-conditioning. Additionally, we aimed to determine whether the pathological impact of isolation stress could be prevented through exposure to exercise alone or to exercise and an enriched environment throughout the isolation period. Two-month-old 5xFAD + and 5xFAD- animals were isolated or group-housed for two and three months. An additional subset of 5xFAD + mice were housed in isolation, housed in isolation with an exercise wheel, or housed in isolation with an exercise wheel and an enriched environment. Both two and three months of isolation stress significantly increased the number of plaques in the hippocampus of 5xFAD + mice, and three months of isolation increased hippocampal BACE1 expression. Isolated animals also displayed a significant cognitive deficit in contextual fear-conditioning, independent of genotype. Furthermore, neither exercise nor an enriched environment were able to prevent these isolation-induced effects. Understanding how stress impacts the onset and progression of AD is critical, as many individuals endure significant stress over their lifespan, including prolonged social isolation, a societal trend likely to worsen with time.

Recent evidence suggests that inflammation-induced decrements in cognitive function can be mitigated via manipulation of excitatory or inhibitory transmission. We tested the ability of the inverse benzodiazepine agonist, MRK-016 (MRK) to protect against LPS-induced deficits in memory acquisition and consolidation, using a contextual fear conditioning (CFC) paradigm. In Experiment One, mice received lipopolysaccharide (LPS) and/or MRK injections prior to CFC training, and were then tested 24h after training. In Experiment Two, animals received similar treatment injections immediately after training, and were tested 24h later. Additionally, hippocampal samples were collected 4h after LPS injections and immediately after testing, to evaluate brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1) mRNA expression. Results indicate that MRK can protect against LPS-induced learning/memory decrements in both paradigms. We also found, in both paradigms, that animals treated with LPS/Saline expressed significantly less BDNF mRNA when compared to Saline/Saline-treated animals 4h after LPS administration, but that MRK did not restore BDNF expression levels. Further, treatment administrations had no effect on IGF-1 mRNA expression at any collection time-point. In summary, MRK-016 can protect against LPS-induced deficits in memory acquisition and consolidation, in this hippocampus-dependent paradigm, though this protection occurs independently of recovery of BDNF expression.

Alzheimer's disease (AD) is a progressive disorder characterized by neuronal and behavioral deterioration. Two hallmark pathologies of AD are amyloid-beta (Aβ) plaques and neurofibrillary tangles, and the presence of such pathology can limit cell-to-cell communication, leading to cognitive deficits, and neuronal cell death. Although Aβ plaques were originally thought to cause the cognitive deficits, more simple forms of Aβ, such as monomers, dimers, tetramers and oligomers, have also been shown to be neurotoxic. Moreover, chronic inflammation has also been implicated in the onset and progression of these AD-related pathologies. The current study was designed to further our understanding of peripheral inflammation-induced AD-like pathology, by administering polyinosinic:polycytidylic acid (poly I:C), a viral mimetic. Mice were administered intraperitoneal injections of poly I:C or saline once daily for 7 consecutive days. Hippocampal tissue from animals receiving poly I:C contained significantly higher levels of the Aβ₁₋₄₂ peptide. Even after ensuring that potential sickness behavior could not confound cognitive testing, we found that animals administered poly I:C displayed significant cognitive deficits in the hippocampus-dependent contextual fear conditioning paradigm. These results confirm our hypothesis that peripheral inflammation can lead to increased levels of hippocampal-Aβ and associated cognitive deficits.

In the current study, the partial NMDA receptor agonist d -cycloserine (DCS) rescued memory consolidation following systemic bacterial endotoxin exposure. DCS failed, however, to restore hippocampal BDNF mRNA levels that were diminished following a systemic administration of LPS, and did not alter NR1 or NR2C NMDA receptor subunit expression. These results extend prior research into the role of DCS in neural-immune interactions, and indicate that the detrimental effects of peripheral LPS administration on consolidation of contextual fear memory may be ameliorated with DCS treatment, though the mechanisms underlying these effects are currently unclear.

An acute LPS challenge immediately following day 1 of shuttlebox training triggered exacerbated central IL-1β production and disrupted memory consolidation and/or further acquisition of the task in 18-month-old mice, compared to 4-month-old controls. These deficits cannot be attributed to alterations in sickness behavior. The findings suggest that age and immune activation combine to impair learning and memory consolidation processes, and that increased central IL-1β production may play a role.

In most environmental models of Parkinson's disease (PD), a single neurodegenerative agent is introduced to cause nigrostriatal dopamine depletion. However, cell loss in human PD often might derive, at least in part, from multiple toxins or vulnerabilities, any one of which alone does not inevitably lead to chronic dopamine depletion. In the present research, male C57BL/6J mice were systemically administered the inflammatory bacterial endotoxin, lipopolysaccharide (LPS) and the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) alone or in combination and the behavior as well as striatal dopamine levels were compared to saline-treated mice. Mice in the combination (LPS + MPTP) group, but not in the single-factor groups, showed both dopamine depletion and parkinsonian symptoms, i.e., reduced stride length, at 4 months post-injection. MPTP alone acutely reduced striatal dopamine levels but this effect was transient as striatal dopamine recovered to normal levels after time (4 months). The LPS-only group showed no dopamine depletion or reduced stride length. These data are consistent with the view that nigrostriatal dopamine neurons might succumb after time to multiple toxic agents that independently may have only a transient, adverse effect.

Prior research suggests that prenatal stress, among other effects, can lead to hyper-reactivity of the offspring's hypothalamic-pituitary-adrenal (HPA) axis and alterations in immune function. These stress-induced changes have been linked to a greater propensity to develop depression or anxiety disorders. Furthermore, prenatally stressed offspring may be more susceptible to certain diseases. The immune alterations induced by prenatal stress exposure may disrupt the normal communication between the immune system, endocrine system, and central nervous system, potentially making prenatally stressed individuals more vulnerable to the negative aspects of immune activation, including cytokine-induced cognitive deficits and anxiety. The present study investigated whether prenatal stress would exaggerate these detrimental effects of peripheral immune activation. We hypothesized that prenatally stressed subjects would be hypersensitive to endotoxin administration and would therefore show exaggerated learning deficits, increased anxiety-like behavior, and increased peripheral and central interleukin-1beta (IL-1beta) levels. The observed results only partially supported our hypotheses, as prenatally stressed subjects showed evidence, albeit modest, of increased anxiety-like behavior following endotoxin administration relative to non-stressed controls. While prenatal stress exposure or lipopolysaccharide (LPS) administration independently impaired learning, the data failed to support the hypothesis that prenatally stressed subjects would show exaggerated cognitive deficits, engendered via enhanced peripheral and central IL-1beta levels, following immune activation. Collectively, the data suggest that although prenatal stress exposure led to increases in anxiety-like behavior following endotoxin exposure, it did not appear to increase susceptibility to LPS-induced cognitive decline or elevations in proinflammatory cytokine production.

Peripheral administration of lipopolysaccharide (LPS) elevates production of pro-inflammatory cytokines, and motivates the expression of sickness behaviors. In this study, we tested the ability of an LPS-derived adjuvant, monophosphoryl lipid A (MPLA), to prevent LPS-induced sickness behaviors in a burrowing paradigm. Testing occurred over a three-day period. Animals received a single injection of either MPLA or saline the first two days of testing. On day three, animals received either LPS or saline. Tissue from the dorsal hippocampus was collected for qRT-PCR to assess expression of IL-1β and IL-4. Results indicate that, during the pre-treatment phase, administration of MPLA induces an immune response sufficient to trigger sickness behaviors. However, we observed that animals pre-treated with MPLA for two days were resistant to LPS-induced sickness behaviors on day three. Results from the qRT-PCR analysis indicated that LPS-treated animals pre-treated with MPLA expressed significantly less IL-1β compared to LPS-treated animals pre-treated with saline. However, we did not observe a significant difference in IL-4 expression between groups. Therefore, results indicate that under the given parameters of the study, MPLA pre-treatment protects against LPS-induced sickness behaviors, at least in part, by decreasing expression of the pro-inflammatory cytokine IL-1β.

Several studies have shown that systemic lipopolysaccharide (LPS) or interleukin-1beta (IL-1beta) may affect performance in various learning tasks, including the Morris water maze. In the current study, female C57BL/6J mice, either 2 months or 1 year of age, were given 5 days of testing followed by 3 days of rest, and then three additional days of testing. Mice either received a single LPS injection on day 1 and saline on days 2-5, LPS injections on days 1-5, or saline injections on days 1-5. Daily LPS administration significantly prolonged latency for the animals to find the platform, and decreased their swimming speed. Year-old mice treated with LPS each day also exhibited significantly higher levels of thigmotaxis in the maze. Despite effects on latency and swim speed, no effect of LPS treatment was observed for distance traveled to the platform or other measures that clearly indicate disruption of learning in the maze. On the other hand, age was a significant factor affecting both latency and distance, with older animals swimming greater distances to find the platform. Additionally, older animals were more adversely affected by daily LPS treatment. In this study, although LPS-induced performance impairments in the Morris water maze were noted, particularly in older animals, these effects were not clearly indicative of learning impairment per se.

Alzheimer's disease (AD) is characterized by neuronal cell death and atrophy in regions of the adult brain, including the hippocampus and cortex, due to formation of amyloid beta (Aβ) plaques and neurofibrillary tangles. The presence of these pathologies can limit normal signaling properties and ultimately lead to learning and memory deficits. Chronic inflammation has been implicated in the onset and progression of these AD-related pathologies. Our study was designed to assess the effects of peripheral inflammation on pathologies associated with AD by using the bacterial endotoxin lipopolysaccharide (LPS). C57BL/6J mice were given intraperitoneal injections of LPS or saline for 1, 3, or 7 consecutive days. Hippocampal tissue from animals receiving LPS contained significantly higher levels of Aβ1-42, a peptide component of AD plaques, than did those from saline control animals. Central and peripheral pro-inflammatory cytokine levels were increased following a single injection of LPS, but retuned to baseline levels before cognitive testing began. We show that one injection of LPS leads to sickness behavior, but 7 consecutive days does not, indicating tolerance to the endotoxin. Cognitive testing was then conducted to determine if whether deficits from increased Aβ1-42 was evident. Results from both Morris water maze and contextual fear conditioning revealed cognitive deficits in LPS-treated mice. In summary, multiple injections of LPS resulted in increased Aβ1-42 in the hippocampus and cognitive deficits in mice.