[Show abstract][Hide abstract] ABSTRACT: We have previously outlined functional interactions, including feedback cycles, between several of the gene products implicated in the pathogenesis of Alzheimer's disease. A number of Alzheimer-related stressors induce neuronal expression of apolipoprotein E (ApoE), β-amyloid precursor protein (βAPP), and fragments of the latter such as amyloid β-peptide (Aβ) and secreted APP (sAPP). These stressors include interleukin-1 (IL-1)-mediated neuroinflammation and glutamate-mediated excitotoxicity. Such circumstances are especially powerful when they transpire in the context of an APOE ε4 allele.
Semi-quantitative immunofluorescence imaging was used to analyze rat brains implanted with IL-1β slow-release pellets, sham pellets, or no pellets. Primary neuronal or NT2 cell cultures were treated with IL-1β, glutamate, Aβ, or sAPP; relative levels of ApoE mRNA and protein were measured by RT-PCR, qRT-PCR, and western immunoblot analysis. Cultures were also treated with inhibitors of multi-lineage kinases--in particular MAPK-p38 (SB203580), ERK (U0126), or JNK (SP600125)--prior to exposure of cultures to IL-1β, Aβ, sAPP, or glutamate.
Immunofluorescence of tissue sections from pellet-implanted rats showed that IL-1β induces expression of βAPP, IL-1α, and ApoE; the latter was confirmed by western blot analysis. These protein changes were mirrored by increases in their mRNAs, as well as in those encoding IL-1β, IL-1β-converting enzyme (ICE), and tumor necrosis factor (TNF). IL-1β also increased ApoE expression in neuronal cultures. It stimulated release of sAPP and glutamate in these cultures too, and both of these agents--as well as Aβ--stimulated ApoE expression themselves, suggesting that they may contribute to the effect of IL-1β on ApoE levels. Inhibitors of MAPK-p38, ERK, and JNK inhibited ApoE induction by all these agents except glutamate, which was sensitive only to inhibitors of ERK and JNK.
Conditions of glial activation and hyperexcitation can elevate proinflammatory cytokines, ApoE, glutamate, βAPP, and its secreted fragments. Because each of these factors promotes glial activation and neuronal hyperexcitation, these relationships have the potential to sustain self-propagating neurodegenerative cycles that could culminate in a progressive neurodegenerative disorder such as Alzheimer's disease.
Journal of Neuroinflammation 12/2011; 8:175. DOI:10.1186/1742-2094-8-175 · 4.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Activated (phosphorylated) mitogen-activated protein kinase p38 (MAPK-p38) and interleukin-1 (IL-1) have both been implicated in the hyperphosphorylation of tau, a major component of the neurofibrillary tangles in Alzheimer's disease. This, together with findings showing that IL-1 activates MAPK-p38 in vitro and is markedly overexpressed in Alzheimer brain, suggest a role for IL-1-induced MAPK-p38 activation in the genesis of neurofibrillary pathology in Alzheimer's disease. We found frequent colocalization of hyperphosphorylated tau protein (AT8 antibody) and activated MAPK-p38 in neurons and in dystrophic neurites in Alzheimer brain, and frequent association of these structures with activated microglia overexpressing IL-1. Tissue levels of IL-1 mRNA as well as of both phosphorylated and non-phosphorylated isoforms of tau were elevated in these brains. Significant correlations were found between the numbers of AT8- and MAPK-p38-immunoreactive neurons, and between the numbers of activated microglia overexpressing IL-1 and the numbers of both AT8- and MAPK-p38-immunoreactive neurons. Furthermore, rats bearing IL-1-impregnated pellets showed a six- to seven-fold increase in the levels of MAPK-p38 mRNA, compared with rats with vehicle-only pellets (P<0.0001). These results suggest that microglial activation and IL-1 overexpression are part of a feedback cascade in which MAPK-p38 overexpression and activation leads to tau hyperphosphorylation and neurofibrillary pathology in Alzheimer's disease.
Neurochemistry International 11/2001; 39(5-6):341-8. DOI:10.1016/S0197-0186(01)00041-9 · 2.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: S100β has been implicated in the formation of dystrophic neurites, overexpressing β-amyloid precursor protein (βAPP), in the β-amyloid plaques of Alzheimer's disease. We assessed the effects of S100β on cell viability of, neurite outgrowth from, and βAPP expression by neurons in primary cultures from fetal rat cortex. S100β (1–10 ng/ml) enhanced neuronal viability (as assessed by increased mitochondrial activity and decreased lactic acid dehydrogenase release) and promoted neurite outgrowth. Higher levels of S100β (100 ng/ml, but not 1 µg/ml) produced qualitatively similar, but less marked, effects. S100β also induced increased neuronal expression of the microtubule-associated protein MAP2, an effect that is consistent with trophic effects of S100β on neurite outgrowth. S100β (10 and 100 ng/ml) induced graded increases in neuronal expression of βAPP and of βAPP mRNA. These results support our previous suggestion that excessive expression of S100β by activated, plaque-associated astrocytes in Alzheimer's disease contributes to the appearance of dystrophic neurites overexpressing βAPP in diffuse amyloid deposits, and thus to the conversion of these deposits into the diagnostic neuritic β-amyloid plaques.