The role of glial inflammatory processes in Alzheimer's disease has been highlighted by recent epidemiological work establishing head trauma as an important risk factor, and the use of anti-inflammatory agents as an important ameliorating factor, in this disease. This review advances the hypothesis that chronic activation of glial inflammatory processes, arising from genetic or environmental insults to neurons and accompanied by chronic elaboration of neuroactive glia-derived cytokines and other proteins, sets in motion a cytokine cycle of cellular and molecular events with neurodegenerative consequences. In this cycle, interleukin-1 is a key initiating and coordinating agent. Interleukin-1 promotes neuronal synthesis and processing of the -amyloid precursor protein, thus favoring continuing deposition of -amyloid, and activates astrocytes and promotes astrocytic synthesis and release of a number of inflammatory and neuroactive molecules. One of these, S100, is a neurite growth-promoting cytokine that stresses neurons through its trophic actions and fosters neuronal cell dysfunction and death by raising intraneuronal free calcium concentrations. Neuronal injury arising from these cytokine-induced neuronal insults can activate microglia with further overexpression of interleukin-1, thus producing feedback amplification and self-propagation of this cytokine cycle. Additional feedback amplification is provided through other elements of the cycle. Chronic propagation of this cytokine cycle represents a possible mechanism for progression of neurodegenerative changes culminating in Alzheimer's disease.
Glutamatergic mechanisms have been investigated in postmortem brain samples from schizophrenics and controls. D-[3H]Aspartate binding to glutamate uptake sites was used as a marker for glutamatergic neurones, and [3H]kainate binding for a subclass of postsynaptic glutamate receptors. There were highly significant increases in the binding of both ligands to membranes from orbital frontal cortex on both the left and right sides of schizophrenic brains. The changes are unlikely to be due to antemortem neuroleptic drug treatment, because no similar changes were recorded in other areas. A predicted left-sided reduction in D-[3H]aspartate binding was refuted at 5% probability, but not at 10%. Previously reported high concentrations of dopamine in left amygdala were strongly associated with low concentrations of D-[3H]aspartate binding in left polar temporal cortex in the schizophrenics. The findings are compatible with an overabundant glutamatergic innervation of orbital frontal cortex in schizophrenia. The results also suggest that schizophrenia may involve left-sided abnormalities in the relationship between temporal glutamatergic and dopaminergic projections to amygdala.
Activated microglia overexpressing interleukin-1 (IL-1) are prominent neuropathological features of Alzheimer's disease. We used computerized image analysis to determine the number of IL-1 alpha-immunoreactive (IL-1 alpha +) microglia in cytoarchitectonic layers of parahippocampal gyrus (Brodmann's area 28) of Alzheimer and control patients. For cortical layers I and II, the numbers of IL-1 alpha + microglia were similar in Alzheimer and control patients. For layers III-VI, the numbers of IL-1 alpha + microglia were higher than that seen in layers I-II for both Alzheimer and control patients. Moreover, for layers III-VI, the number of IL-1 alpha + microglia in Alzheimer patients was significantly greater than that in control patients (relative Alzheimer values of threefold for layer III-V and twofold for layer VI; P < 0.05 in each case). The cortical laminar distribution of IL-1 alpha + microglia in Alzheimer patients correlated with the cortical laminar distribution of beta-amyloid precursor protein-immunoreactive (beta-APP+) neuritic plaques found in Alzheimer patients (r = 0.99, P < 0.005). Moreover, the cortical laminar distribution of IL-1 alpha + microglia in control patients also correlated with the cortical laminar distribution of beta-APP+ neuritic plaques found in Alzheimer patients (r = 0.91, P < 0.05). These correlations suggest that pre-existing laminar distribution patterns of IL-1 alpha + microglia (i.e. that seen in control patients) are important in determining the observed laminar distribution of beta-APP+ neuritic plaques in Alzheimer patients. These findings provide further support for our hypothesis that IL-1 is a key driving force in neuritic plaque formation in Alzheimer's disease.
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