No abstract

One of the major challenges in neuroscience is to identify the changes which accompany aging and which contribute to the well-documented age-related deterioration in cognitive function. This is a particular challenge in the light of the vast array of reported changes, which include morphological changes like synaptic and perhaps cell loss, alteration in membrane composition and the resultant changes in function of membrane proteins, modulation of the hypothalamo-pituitary axis, impaired calcium homoeostatic mechanisms, alteration in enzyme function and decreased neurotransmitter release. In the past few years, evidence suggesting that an aged brain exhibits signs of oxidative stress and inflammatory stress has been accumulating, and recent evidence using microarray analysis has added support to this view. In this paper, we provide evidence to suggest that vitamin D3 acts as an anti-inflammatory agent and reverses the age-related increase in microglial activation and the accompanying increase in IL-1beta (interleukin-1beta) concentration.

Among the changes which occur in the brain with age is an increase in hippocampal concentration of proinflammatory cytokines like interleukin-1beta (IL-1beta) and an increase in IL-1beta-induced signaling. Here we demonstrate that the increase in IL-1beta concentration is accompanied by an increase in expression of IL-1 type I receptor (IL-1RI) and an age-related increase in microglial activation, as shown by increased expression of the cell surface marker, major histocompatibility complex II (MHCII) and increased MHCII staining. The evidence indicates that these age-related changes were abrogated in hippocampus of aged rats treated with dexamethasone and vitamin D3. Similarly, the age-related increases in activation of the stress-activated protein kinase, c-Jun N-terminal kinase (JNK), as well as caspase-3 and PARP were all attenuated in hippocampal tissue prepared from rats that received dexamethasone and vitamin D3. The data indicate that dexamethasone and vitamin D3 ameliorated the age-related increase in IFNgamma and suggest that IFNgamma may be the trigger leading to microglial activation, since it increases MHCII mRNA and IL-1beta release from cultured glia. In parallel with its ability to decrease microglial activation in vivo, we report that treatment of cultured glia with dexamethasone and vitamin D3 blocked the lipopolysaccharide increased MHCII mRNA and IL-1beta concentration, while the IL-1beta-induced increases in activation of JNK and caspase 3 in cultured neurons were also reversed by treatment with dexamethasone and vitamin D3. The data suggest that the antiinflammatory effect of dexamethasone and vitamin D3 derives from their ability to downreguate microglial activation.

In the last few years, several research groups have reported that neuroinflammation is one feature common to several neurodegenerative diseases and that similar, although perhaps less profound, neuroinflammatory changes also occur with age. Age is the greatest risk factor in many neurodegenerative diseases, and the possibility exists that the underlying age-related neuroinflammation may contribute to this increased risk. Several animal models have been used to examine this possibility, and it is now accepted that, under experimental conditions in which microglial activation is up-regulated, responses to stressors are exacerbated. In the present article, these findings are discussed and data are presented from in vitro and in vivo experiments which reveal that responses to Abeta (amyloid beta-peptide) are markedly up-regulated in the presence of LPS (lipopolysaccharide). These, and previous findings, point to a vulnerability associated with inflammation and suggest that, even though inflammation may not be the primary cause of neurodegenerative disease, its treatment may decelerate disease progression.

, et al.. The deficit in long-term potentiation induced by chronic administration of amyloid-β-is attenuated by treatment of rats with a novel phospholipid-based drug formulation, VP025. Experimental Gerontology, Elsevier, 2009, 44 (4), pp.300. <10.1016/j.exger.2008.12.001>. Accepted ManuscriptThe deficit in long-term potentiation induced by chronic administration of amyloid-β-is attenuated by treatment of rats with a novel phospholipid-based drug formulation, VP025 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPTThe deficit in long-term potentiation induced by chronic administration of amyloid--is attenuated by treatment of rats with a novel phospholipid-based drug formulation, VP025 ACCEPTED MANUSCRIPT ABSTRACTAmyloid-(A ) peptides, the primary component of the amyloid plaques in Alzheimer's disease (AD), exert profound effects on neurons in vitro and negatively impact on neuronal function in vivo. One of the consequences of increased A in the brain, either as a result of overexpression of the precursor amyloid precursor protein in transgenic mice, or injection into the brain is a decrease in one form of synaptic plasticity, long-term potentiation (LTP) in the hippocampus. Here we investigated the effect of infusion of A for 28 days on LTP in dentate gyrus of rats and demonstrate that it was profoundly decreased compared with control-treated rats. We show that this effect is accompanied by increased activity of caspase 3, which is an indicator of cell stress. Significantly these changes were attenuated in animals which were pretreated with particles incorporating phosphatidylglycerol (VP025) and the evidence indicated that even when treatment was given 2 weeks after the start of the A infusion, VP025 was capable of attenuating A -induced changes. The evidence suggests that activation of caspase 3 was mediated by an A -induced increase in sphingomyelinase, with the subsequent production of ceramide which is known to have a detrimental effect on neuronal function.