Search

The NLRP3 inflammasome forms in response to a diverse range of stimuli and is responsible for the processing and release of interleukin-1β (IL-1β) from the immunocompetent cells of the brain. The pathological peptide of Alzheimer's disease, amyloid beta (Aβ), induces formation of the NLRP3 inflammasome in a manner dependent on the family of proteases, cathepsins; however, the pathway by which cathepsins induce formation of the inflammasome has not yet been elucidated. In this study, we show that Aβ treatment of primary rat glial cultures increases cathepsin activation in the cytosol, formation of the NLRP3 inflammasome, caspase 1 activation and IL-1β release. We also show that a second NOD-like protein, NLRP10, is found bound to apoptosis-associated speck-like protein under resting conditions; however, with Aβ treatment, both in vitro and in vivo, NLRP10 is decreased. Further to these data, we show that cathepsins are capable of degrading NLRP10 and that treatment of glial cultures with recombinant NLRP10 reduces Aβ-induced caspase 1 activation and IL-1β release. We propose that Aβ-induced cathepsin released into the cytosol degrades NLRP10, thus allowing dissociation of NLRP3 and formation of the inflammasome.

In view of the increase in the aging population and the unavoidable parallel increase in the incidence of age-related neurodegenerative diseases, a key challenge in neuroscience is the identification of clinical signatures which change with age and impact on neuronal and cognitive function. Early diagnosis offers the possibility of early therapeutic intervention, thus magnetic resonance imaging (MRI) is potentially a powerful diagnostic tool. We evaluated age-related changes in relaxometry, blood flow, and blood-brain barrier (BBB) permeability in the rat by magnetic resonance imaging and assessed these changes in the context of the age-related decrease in synaptic plasticity. We report that T2 relaxation time was decreased with age; this was coupled with a decrease in gray matter perfusion, suggesting that the observed microglial activation, as identified by increased expression of CD11b, MHCII, and CD68 by immunohistochemistry, flow cytometry, or polymerase chain reaction (PCR), might be a downstream consequence of these changes. Increased permeability of the blood-brain barrier was observed in the perivascular area and the hippocampus of aged, compared with young, rats. Similarly there was an age-related increase in CD45-positive cells by flow cytometry, which are most likely infiltrating macrophages, with a parallel increase in the messenger mRNA expression of chemokines IP-10 and MCP-1. These combined changes may contribute to the deficit in long-term potentiation (LTP) in perforant path-granule cell synapses of aged animals., (Copyright © 2012 Elsevier Inc. All rights reserved.)

There is a well-established literature indicating a relationship between iron in brain tissue and Alzheimer's disease (AD). More recently, it has become clear that AD is associated with neuroinflammatory and oxidative changes which probably result from microglial activation. In this study, we investigated the correlative changes in microglial activation, oxidative stress, and iron dysregulation in a mouse model of AD which exhibits early-stage amyloid deposition. Microfocus X-ray absorption spectroscopy analysis of intact brain tissue sections prepared from AβPP/PS1 transgenic mice revealed the presence of magnetite, a mixed-valence iron oxide, and local elevations in iron levels in tissue associated with amyloid-β-containing plaques. The evidence indicates that the expression of markers of microglial activation, CD11b and CD68, and astrocytic activation, GFAP, were increased, and were histochemically determined to be adjacent to amyloid-β-containing plaques. These findings support the contention that, in addition to glial activation and oxidative stress, iron dysregulation is an early event in AD pathology.

Age is characterized by deficits in synaptic function identified by decreased performance of aged animals in spatial learning tasks and reduced ability of animals to sustain long term potentiation (LTP). Several cellular and molecular events are correlated with these deficits, many of which are indicative of age-related neuroinflammatory and oxidative cell stress. It is significant that agents which decrease microglial activation are commonly associated with restoration of function. We set out to examine whether the n-3 polyunsaturated fatty acid docosapentaenoic acid (DPA), which is a metabolite of eicosapentaenoic acid (EPA), could modulate the age-related increase in microglial activation and the associated increase in oxidative changes and therefore impact on synaptic function in aged rats. We demonstrate that docosapentaenoic acid possesses neurorestorative effects and is capable of downregulating microglial activation. The data show that it also decreases the coupled activation of sphingomyelinase and caspase 3, probably because of its ability to decrease age-related oxidative changes, and consequently attenuates the age-related decrease in spatial learning and long-term potentiation., (Copyright © 2011 Elsevier Inc. All rights reserved.)