Beatrice Hauss-Wegrzyniak

Chronic neuroinflammation in rats reproduces components of the neurobiology of Alzheimer's disease

Inflammatory processes may play a critical role in the pathogenesis of the degenerative changes and cognitive impairments associated with Alzheimers disease (AD). In the present study, lipopolysaccharide (LPS) from the cell wall of gram-negative bacteria was used to produce chronic, global inflammation within the brain of young rats. Chronic infusion of LPS (0.25 microgram/h) into the 4th ventricle for four weeks produced (1) an increase in the number of glial fibrillary acidic protein-positive activated astrocytes and OX-6-positive reactive microglia distributed throughout the brain, with the greatest increase occurring within the temporal lobe, particularly the hippocampus, (2) an induction in interleukin-1 beta, tumor necrosis factor-alpha and beta-amyloid precursor protein mRNA levels within the basal forebrain region and hippocampus, (3) the degeneration of hippocampal CA3 pyramidal neurons, and (4) a significant impairment in spatial memory as determined by decreased spontaneous alternation behavior on a T-maze.

Chronic Brain Inflammation Results in Cell Loss in the Entorhinal Cortex and Impaired LTP in Perforant Path-Granule Cell Synapses

Alzheimers disease (AD) is characterized by chronic neuroinflammation, significant temporal lobe cell loss, and dementia. We investigated the influence of chronic neuroinflammation produced by chronic infusion of lipopolysaccharide (LPS) into the fourth ventricle for 4 weeks upon the induction and maintenance of long-term potentiation (LTP) in the dentate gyrus of the hippocampus, a well-characterized model of cellular synaptic plasticity. We also examined for pyramidal cell loss within the entorhinal cortex an area of the brain that contains the cell bodies of the perforant path. The results demonstrate that chronic neuroinflammation results in the loss of pyramidal cells within layers II and III of the entorhinal cortex and a significant attenuation of LTP within the dentate gyrus. Similar changes may underlie the temporal lobe pathology and dementia associated with AD.

Brain inflammatory response induced by intracerebroventricular infusion of lipopolysaccharide: An immunohistochemical study

Inflammatory processes may play a critical role in the pathogenesis of the degenerative changes associated with Alzheimers disease (AD). In the present study, we used an animal model of brain inflammation in order to study a possible mechanism involved in AD. Lipopolysaccharide (LPS) was used to produce global microglial reactivity within the brain of young rats. Time-dependent changes in the inflammatory reaction and the participation of glial cells after acute injection of LPS (50 or 100 microg) into the lateral ventricle or the fourth ventricle were compared with the chronic infusion of LPS (0.15, 0.5, 1.5 or 5.0 microg/h) into the fourth ventricle (14 days). Several immunohistochemical markers were used to characterize the microglial response. Acute and chronic exposure to LPS induced major histocompatibility complex class II (MHC II) antigen expression, detected with OX-6 antibody, in a sub-population of microglial cells in defined brain areas. The morphological features and distribution of OX-6 positive cells observed in the proximity of the cannula track after LPS injection into the lateral ventricle suggested the recruitment of monocytes/macrophages from the periphery. The activation of the resident microglial cells was delayed and mainly concentrated within the temporal lobe regions and the limbic system. Chronic infusion to LPS into the fourth ventricle induced a comparable activation of microglial cells. Quantitative analysis of OX-6 positive cells showed a dose-dependent response to LPS exposure.

Behavioral and ultrastructural changes induced by chronic neuroinflammation in young rats.

We investigated the ultrastructural, immunohistochemical, biochemical and behavioral effects of chronic neuroinflammation in young rats produced by injection of lipopolysaccharide (LPS) into the 4th ventricle. The 37-day infusion of LPS impaired spatial memory but not object recognition ability. Electron microscopic studies of neurons within the hippocampus identified numerous paired cisternae of the rough endoplasmic reticulum (RER) and other ultrastructural changes that suggested impaired or reduced synthesis of cellular proteins within the cytoplasm. Immunohistochemical staining found numerous highly activated microglia distributed throughout the cingulate gyrus, entorhinal cortex, hippocampus and dentate gyrus. This animal model may be useful to test potential pharmacotherapies that are directed at the prevention of the cytotoxic consequences of chronic neuroinflammation associated with normal aging or Alzheimers disease.

Peripheral administration of novel anti-inflammatories can attenuate the effects of chronic inflammation within the CNS.

In the present study we investigated whether nitroflurbiprofen (NFP) or nitro-aspirin can reduce the inflammatory response induced by continuous infusion of lipopolysaccharide (LPS) into the fourth ventricular space of the rats brain for 30 days. The chronic LPS infusion produced an extensive inflammation that was particularly evident in the hippocampus, subiculum and entorhinal and piriform cortices. Daily peripheral administration of NFP dose-dependently, and significantly, attenuated the brain inflammation as indicated by the decreased density and reactive state of microglial cells. Daily peripheral administration of nitro-aspirin also attenuated the brain inflammation, but to a much lesser degree than NFP. The results demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs) could reduce brain inflammation and that NFP is an effective anti-inflammatory agent.

Attenuation of chronic neuroinflammation by a nitric oxide-releasing derivative of the antioxidant ferulic acid

Chronic neuroinflammation and oxidative stress contribute to the neurodegeneration associated with Alzheimers disease and represent targets for therapy. Ferulic acid is a natural compound that expresses antioxidant and anti‐inflammatory activities. Nitric oxide is also a key modulator of inflammatory responses. Grafting a nitric oxide‐releasing moiety onto anti‐inflammatory drugs results in enhanced anti‐inflammatory activity. We compared the effectiveness of ferulic acid with a novel nitric oxide‐releasing derivative of ferulic acid in an animal model of chronic neuroinflammation that reproduces many interesting features of Alzheimers disease. Lipopolysaccharide was infused into the 4th ventricle of young rats for 14 days. Various doses of ferulic acid or its nitric oxide‐releasing derivative were administered daily. Both drugs produced a dose‐dependent reduction in microglia activation within the temporal lobe. However, the nitric oxide‐releasing ferulic acid derivative was significantly more potent. If we delayed the initiation of therapy for 14 days, we found no reduction in microglial activation. In addition, both drugs demonstrated antioxidant and hydroxyl radical scavenging abilities in in vitro studies. Overall, our results predict that a treatment using nitric oxide‐releasing ferulic acid may attenuate the processes that drive the pathology associated with Alzheimers disease if the treatment is initiated before the neuroinflammatory processes can develop.

Chronic brain inflammation leads to a decline in hippocampal NMDA-R1 receptors

BackgroundNeuroinflammation plays a prominent role in the progression of Alzheimers disease and may be responsible for degeneration in vulnerable regions such as the hippocampus. Neuroinflammation is associated with elevated levels of extracellular glutamate and potentially an enhanced stimulation of glutamate N-methyl-D-aspartate receptors. This suggests that neurons that express these glutamate receptors might be at increased risk of degeneration in the presence of chronic neuroinflammation.MethodsWe have characterized a novel model of chronic brain inflammation using a slow infusion of lipopolysaccharide into the 4th ventricle of rats. This model reproduces many of the behavioral, electrophysiological, neurochemical and neuropathological changes associated with Alzheimers disease.ResultsThe current study demonstrated that chronic neuroinflammation is associated with the loss of N-methyl-D-aspartate receptors, as determined both qualitatively by immunohistochemistry and quantitatively by in vitro binding studies using [3H]MK-801, within the hippocampus and entorhinal cortex.ConclusionThe gradual loss of function of this critical receptor within the temporal lobe region may contribute to some of the cognitive deficits observed in patients with Alzheimers disease.

APP and PS-1 mutations induce brain oxidative stress independent of dietary cholesterol: implications for Alzheimer's disease

Epidemiological and biochemical studies strongly implicate a role for cholesterol in the pathogenesis of Alzheimers disease (AD). Mutation in the PS-1 and APP genes, which increases production of the highly amyloidogenic amyloid beta-peptide (Abeta42), is the major cause of familial AD. The AD brain is under significant oxidative stress, including protein oxidation and lipid peroxidation. In the present study, protein oxidation and lipid peroxidation were compared in the brain homogenates from knock-in mice expressing mutant human PS-1 and APP in relation to the intake of dietary cholesterol. The APP and PS-1 mice displayed increased oxidative stress as measured by protein oxidation and lipid peroxidation, independent of dietary cholesterol. These results are discussed with reference to proposed therapeutic strategies of AD.

LPS-induced neuroinflammatory effects do not recover with time.

Inflammatory processes develop in the vicinity of the neuro-pathological hallmarks associated with Alzheimers disease (AD) and may play a role in the progression of the disease and its clinical expression. We have previously reported that chronic infusion of LPS into the fourth ventricle of rat brains reproduced many of the inflammatory and pathological changes seen in the brain of AD patients. In the current study, we used the same animal model to investigate the effects of longer infusion of LPS and whether these effects could recover over time. The results show that doubling the time of LPS infusion did not increased the inflammatory reaction and did not produce a significantly greater behavioral impairment. Waiting for 37 days after the cessation of the LPS infusion did not decrease the density of activated microglia and did not improve performances in the Morris water maze task. The results suggest that inflammation may contribute to the pathogenic mechanisms that underlie the clinical expression of AD.

Mechanisms to prevent the toxicity of chronic neuroinflammation on forebrain cholinergic neurons.

Inflammatory processes may play an important role in the degeneration of basal forebrain cholinergic cells Alzheimers disease. We infused the proinflammagen lipopolysaccharide into the basal forebrain of young rats and determined whether the chronic administration of two novel non-steroidal anti-inflammatory drugs or a pan-caspase synthesis inhibitor, z-Val-Ala-Asp(OMe)-fluoromethyl ketone (zVAD), could provide neuroprotection from the cytotoxic effects of the neuroinflammation. Chronic lipopolysaccharide infusions decreased choline acetyltransferase activity and increased the number of activated microglia within the basal forebrain region. The level of caspases 3, 8 and 9 was increased in ventral caudate/putamen. Non-steroidal anti-inflammatory drug therapy attenuated the toxicity of the inflammation upon cholinergic cells and reduced caspases 3, 8 and 9 activity in the caudate/putamen. zVAD treatment significantly decreased the levels of caspases 3, 8 and 9 but did not provide neuroprotection for the cholinergic neurons. These results suggest that prostaglandins contribute to the degeneration of forebrain cholinergic neurons in Alzheimers disease.