Interleukin 1, an immune response-generated cytokine that stimulates astrocyte proliferation and reactivity (astrogliosis), was present in up to 30 times as many glial cells in tissue sections of brain from patients with Down syndrome and Alzheimer disease compared with age-matched control subjects. Most interleukin 1-immunoreactive glia in Down syndrome and Alzheimer disease were classified as microglia. The number of interleukin 1 immunoreactive neurons did not appear to differ in Down syndrome and Alzheimer disease compared with control brain. Numerous temporal lobe astrocytes in Alzheimer disease and postnatal Down syndrome were intensely interleukin 1-, S-100-, and glial fibrillary acidic protein-immunoreactive and had reactive structure. Interleukin 1 levels in Alzheimer disease temporal lobe homogenates were elevated, as were the levels of S-100 and glial fibrillary acidic protein, two proteins reportedly elevated in reactive astrocytes. These data suggest that increased expression of S-100 in Down syndrome, resulting from duplication of the gene on chromosome 21 that encodes the I6 subunit of S-100, may be augmented by elevation of interleukin 1. As a corollary, the astrogliosis in Alzheimer disease may be promoted by elevation of interleukin 1.

The presence of tangles of abnormally phosphorylated tau is a characteristic of Alzheimer's disease (AD), and the loss of synapses correlates with the degree of dementia. In addition, the overexpression of interleukin-1 (IL-1) has been implicated in tangle formation in AD. As a direct test of the requirement for IL-1 in tau phosphorylation and synaptophysin expression, IL-1 actions in neuron-microglia cocultures were manipulated. Activation of microglia with secreted beta-amyloid precursor protein or lipopolysaccharide elevated their expression of IL-1alpha, IL-1beta, and tumor necrosis factor alpha (TNFalpha) mRNA. When such activated microglia were placed in coculture with primary neocortical neurons, a significant increase in the phosphorylation of neuronal tau was accompanied by a decline in synaptophysin levels. Similar effects were evoked by treatment of neurons with recombinant IL-1beta. IL-1 receptor antagonist (IL-1ra) as well as anti-IL-1beta antibody attenuated the influence of activated microglia on neuronal tau and synaptophysin, but anti-TNFalpha antibody was ineffective. Some effects of microglial activation on neurons appear to be mediated by activation of p38 mitogen-activated protein kinase (p38-MAPK), because activated microglia stimulated p38-MAPK phosphorylation in neurons, and an inhibitor of p38-MAPK reversed the influence of IL-1beta on tau phosphorylation and synaptophysin levels. Our results, together with previous observations, suggest that activated microglia may contribute to neurofibrillary pathology in AD through their production of IL-1, activation of neuronal p38-MAPK, and resultant changes in neuronal cytoskeletal and synaptic elements.

Microglia make up the innate immune system of the central nervous system and are key cellular mediators of neuroinflammatory processes. Their role in central nervous system diseases, including infections, is discussed in terms of a participation in both acute and chronic neuroinflammatory responses. Specific reference is made also to their involvement in Alzheimer's disease where microglial cell activation is thought to be critically important in the neurodegenerative process.

No abstract

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.

Elevation of the proinflammatory cytokine Interleukin-1 (IL-1) is an integral part of the local tissue reaction to central nervous system (CNS) insult. The discovery of increased IL-1 levels in patients following acute injury and in chronic neurodegenerative disease laid the foundation for two decades of research that has provided important details regarding IL-1's biology and function in the CNS. IL-1 elevation is now recognized as a critical component of the brain's patterned response to insults, termed neuroinflammation, and of leukocyte recruitment to the CNS. These processes are believed to underlie IL-1's function in the setting of acute brain injury, where it has been ascribed potential roles in repair as well as in exacerbation of damage. Explorations of IL-1's role in chronic neurodegenerative disease have mainly focused on Alzheimer disease (AD), where indirect evidence has implicated it in disease pathogenesis. However, recent observations in animal models challenge earlier assumptions that IL-1 elevation and resulting neuroinflammatory processes play a purely detrimental role in AD, and prompt a need for new characterizations of IL-1 function. Potentially adaptive functions of IL-1 elevation in AD warrant further mechanistic studies, and provide evidence that enhancement of these effects may help to alleviate the pathologic burden of disease.

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Cerebral amyloid angiopathy (CAA) is characterized by the deposition of the amyloid beta-protein (A beta) within cerebral vessels. The involvement of different brain areas in CAA follows a hierarchical sequence similar to that of Alzheimer-related senile plaques. Alzheimer's disease patients frequently exhibit CAA. The expansion of CAA in AD often shows the pattern of full-blown CAA. The deposition of A beta within capillaries distinguishes two types of CAA. One with capillary A beta-deposition is characterized by a strong association with the apolipoprotein E (APOE) epsilon 4 allele and by its frequent occurrence in Alzheimer's disease cases whereas the other one lacking capillary A beta-deposits is not associated with APOE epsilon 4. Capillary CAA can be seen in every stage of CAA or AD-related A beta-deposition. AD cases with capillary CAA show more widespread capillary A beta-deposition than non-demented cases as well as capillary occlusion. In a mouse model of CAA, capillary CAA was associated with capillary occlusion and cerebral blood flow disturbances. Thus, blood flow alterations with subsequent hypoperfusion induced by CAA-related capillary occlusion presumably point to a second mechanism in which A beta adversely affects the brain in AD in addition to its direct neurotoxic effects.