W. Sue T. Griffin

Microglia and neuroinflammation: a pathological perspective

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 Alzheimers disease where microglial cell activation is thought to be critically important in the neurodegenerative process.

Interleukin-1 Expression in Different Plaque Types in Alzheimer's Disease: Significance in Plaque Evolution

Abstract. The histologically apparent polymorphism of plaques containing β-amyloid in Alzheimers disease is thought to represent different stages in plaque evlution. β-amyloid-immunopostitive plaques were classified according to the pattern of β-amyloid distribution (diffuse vs dense-core) and the presence or absence of dystrophic β-amyloid precursor protein-immunopositive (β-APP+) neurites (neuritic vs non-neuritic). The potential contribution of microgilia-derived interleukin-1 (IL-1), an immune response cytokine that induces synthesis and processing of β-APP, to the possible sequential development of these plaque types was examined through determination of the number of IL-1α+ microglia associated with each of four identified plaque types. Diffuse non-neuritic plaques had the least dense and most widely dispersed β-amyloid, did not exhibit β-APP+ dystrophic neurites, but most (78%) contained activated IL-1α+ microglia (2 γ 0.2/Plaque; mean γ SEM). Diffuse neuritic plaques had more dense, but still widely dispersed β-amyloid, displayed a profusion of β-APP+ dystrophic neurites, and had the greatest numbers of associated activated IL-1α+ microglia (4 γ 0.4/plaque). Dense-core, non-neuritic plaques had compact β-amyloid, lacked associated diffuse β-amyloid, and were devoid of both IL-1α+ microglia and β-APP+ dystrophic neurites. These results suggest an important immunological component in the evolution of amyloid-contining plaques in Alzheimers disease and further suggest that IL-1-expressing cells are necessary to intitiate dystrophic neurite formation in diffuse β-amyloid deposits. Our data indicate that activation of microglia with expression of IL-1 in Alzheimers disease is required to drive the metamorphosis of diffuse non-neuritic β-amyloid deposits to the characteristic and diagnostic neuritic plaques of Alzheimers disease.

Glia and their cytokines in progression of neurodegeneration

A glia-mediated, inflammatory immune response is an important component of the neuropathophysiology of Alzheimers disease, of the midlife neurodegeneration of Downs syndrome, and of other age-related neurodegenerative conditions. All of these conditions are associated with early and often dramatic activation of, and cytokine overexpression in, microglia and astrocytes, sometimes decades before pathological changes consistent with a diagnosis of Alzheimers disease are apparent, as in patients with Downs syndrome or head injury. Brains of normal elderly individuals also often show Alzheimer-type neuropathological changes, although to a lesser degree than those seen in Alzheimers disease itself. These normal age-related glial changes, likely a response to the normal wear and tear of the aging process, raise the threshold of glial activation and thus may explain the fact that even genetically determined Alzheimers disease, resulting from genetic mutations such as those in beta-amyloid precursor protein and presenilins or from genetic duplication such as of chromosome 21, only shows the full manifestation of the disease decades after birth. In the more common sporadic form of Alzheimers disease, age-related increases in glial activation and expression of cytokines may act in synergy with other genetic and acquired environmental risks to culminate in the development of disease.

Glial cytokines in Alzheimer's disease: Review and pathogenic implications

The roles of activated glia and of glial cytokines in the pathogenesis of Alzheimers disease are reviewed. Interleukin-1 (IL-1), a microglia-derived acute phase cytokine, activates astrocytes and induces expression of the astrocyte-derived cytokine, S100 beta, which stimulates neurite growth (and thus has been implicated in neuritic plaque formation) and increases intracellular free calcium levels. Interleukin-1 also upregulates expression and processing of beta-amyloid precursor proteins (beta-APPs) (thus favoring beta-amyloid deposition) and induces expression of alpha 1-antichymotrypsin, thromboplastin, the complement protein C3, and apolipoprotein E, all of which are present in neuritic plaques. These cytokines, and the molecular and cellular events that they engender, form a complex of interactions that may be capable of self-propagation, leading to chronic overexpression of glial cytokines with neurodegenerative consequences. Self-propagation may be facilitated by means of several reinforcing feedback loops. beta-Amyloid, for instance, directly activates microglia, thus inducing further IL-1 production, and activates the complement system, which also leads to microglial activation with IL-1 expression. Self-propagation also could result when S100 beta-induced increases in intraneuronal free calcium levels lead to neuronal injury and death with consequent microglial activation. Such chronic, self-propagating, cytokine-mediated molecular and cellular reactions would explain the progressive neurodegeneration and dementia of Alzheimers disease.

Interleukin-1, neuroinflammation, and Alzheimer’s disease

Interleukin-1 (IL-1)-1) is a pluripotent immunomodulatory cytokine that has an initiating role in cellular and humoral immunity in the periphery. Il-1 is overexpressed in Alzheimer brain, and this overexpression is directly related to plaque formation and progression, nonsensical growth of dystrophic neurites, and neuronal overexpression of acetylcholinesterase. IL-1 has a number of actions relevant to Alzheimers disease, including excessive expression of neuronal Abeta precursor protein and other plaque-associated proteins, and induction of astrocyte activation and astrocytic overexpression of S100B. These latter events may be related to the overgrowth of dystrophic neurites in neuritic plaques, a necessary event for conversion of diffuse Abeta deposits into the neuritic amyloid plaques diagnostic of Alzheimers disease. Four new genetic studies underscore the relevance of IL-1 to Alzheimer pathogenesis, showing that homozygosity of a specific polymorphism in the IL-1A gene at least triples Alzheimer risk, especially for an earlier age of onset and in combination with homozygosity for another polymorphism in the IL-1B gene.

In vivo and in vitro evidence supporting a role for the inflammatory cytokine interleukin-1 as a driving force in Alzheimer pathogenesis

Interleukin-1 (IL-1), an inflammatory cytokine overexpressed in the neuritic plaques of Alzheimers disease, activates astrocytes and enhances production and processing of beta-amyloid precursor protein (beta-APP). Activated astrocytes, overexpressing S100 beta, are a prominent feature of these neuritic plaques, and the neurite growth-promoting properties of S100 beta have been implicated in the formation of dystrophic neurites overexpressing beta-APP in neuritic plaques. These facts collectively suggest that elevated levels of the inflammatory cytokine IL-1 drive S100 beta and beta-APP overexpression and dystrophic neurite formation in Alzheimers disease. To more directly assess this driver potential for IL-1, we analyzed IL-1 induction of S100 beta expression in vivo and in vitro, and of beta-APP expression in vivo. Synthetic IL-1 beta was injected into the right cerebral hemispheres of 13 rats. Nine additional rats were injected with phosphate-buffered saline, and seven rats served as uninjected controls. The number of astrocytes expressing detectable levels of S100 beta in tissue sections from IL-1-injected brains was 1.5 fold that of either control group (p < 0.01), while tissue S100 beta levels were approximately threefold that of controls (p < 0.05). The tissue levels of two beta-APP isoforms (approximately 130 and 135 kDa) were also significantly elevated in IL-1-injected brains (p < 0.05). C6 glioma cells, treated in vitro for 24 h with either IL-1 beta or IL-1 alpha, showed significant increases in both S100 beta and S100 beta mRNA levels. These results provide evidence that IL-1 upregulates both S100 beta and beta-APP expression, in vivo and vitro, and support the idea that overexpression of IL-1 in Alzheimers disease drives astrocytic overexpression of S100 beta, favoring the growth of dystrophic neurites necessary for evolution of diffuse amyloid deposits into neuritic beta-amyloid plaques.

Increased S100β neurotrophic activity in Alzheimer's disease temporal lobe

The confirming diagnosis of Alzheimers disease includes an assessment of the concentration of neuritic plaques in the temporal lobe of the brain. The presence of abnormal levels of neurotrophic factors in Alzheimers disease is one possible explanation for the increased concentration of aggregates of overgrown neurites in the neuritic plaques of Alzheimers disease. The protein S100 beta, a neurotrophic factor produced by astroglia in the brain, induces neurite outgrowth in cerebral cortical neurons. The generation of specific S100 beta antibodies, the cloning of a full-length cDNA encoding the S100 beta mRNA, and the development of a neurite extension assay system for S100 beta allowed testing of the hypothesis that Alzheimers disease S100 beta expression is elevated in brain temporal lobe where neuritic plaques are concentrated. The levels of S100 beta protein, mRNA, and specific neurotrophic activity were elevated 10-20-fold in extracts of temporal lobe from autopsy samples of Alzheimers disease patients compared to those of aged control patients. The cells containing the increased S100 beta were reactive astrocytes; the neuritic plaques were surrounded by S100 beta-containing astrocytes. The elevated levels of S100 beta provides a link between the prominent reactive gliosis and neuritic plaque formation in this common disease of the elderly and raises the possibility that S100 beta contributes to Alzheimers disease neuropathology.

S100β expression in Alzheimer's disease: Relation to neuropathology in brain regions

S100 beta levels in tissue homogenates and distribution of S100 beta-containing activated astrocytes were examined by S100 beta-specific ELISA and immunohistochemistry, respectively, in brain regions exhibiting many, some, few, or no neuritic plaques in Alzheimers disease (AD). Compared to samples collected at similar postmortem intervals from control patients of similar ages, S100 beta levels were elevated in specific brain regions from AD patients, and the overexpression of S100 beta correlated relatively well with the pattern of regional involvement by neuritic plaques. The largest increases in S100 beta levels were in hippocampus and temporal lobe, followed by frontal lobe and pons, with no elevation in occipital lobe or cerebellum. Immunohistochemical analysis showed S100 beta localization primarily in activated astrocytes surrounding neuritic plaques. These results demonstrate that S100 beta overexpression is brain region-specific and related to astrocyte activation and suggest that elevation of S100 beta above some threshold is related to the degree of neuropathological involvement of different brain regions in AD.

Aging-associated Changes in Human Brain

A wide varicty of anatomic and histological alterations are common in brains of aged individuals. However, identification of intrinsic aging changes—as distinct from changes resulting from cumulative environmental insult—is problematic. Some degree of neuronal and volume loss would appear to be inevitable, but recent studies have suggested that the magnitudes of such changes are much less than previously thought, and studies of dendritic complexity in cognitively intact individuals suggest continuing neuronal plasticity into the eighth decade. A number of vascular changes become more frequent with age, many attributable to systemic conditions such as hypertension and atherosclerosis. Age-associated vascular changes not clearly linked to such conditions include hyaline arteriosclerotic changes with formation of arterial tortuosities in small intracranial vessels and the radiographic changes in deep cerebral white matter known as “leukoaralosis.” Aging is accompanied by increases in glial cell activation, in oxidative damage to proteins and lipids, in irreversible protein glycation, and in damage to DNA, and such changes may underlie in part the age-associated increasing incidence of “degenerative” conditions such as Alzheimer disease and Parkinson disease. A small number of histological changes appear to be universal in aged human brains. These include increasing numbers of corpora amylacea within astrocytic processes near blood-brain or cerebrospinal fluid-brain interfaces, accumulation of the “aging” pigment lipofuscin in all brain regions, and appearance of Alzheimer-type neurofibrillary tangles (but not necessarily amyloid plaques) in mesial temporal structures.

Increased Neuronal β-Amyloid Precursor Protein Expression in Human Temporal Lobe Epilepsy: Association with Interleukin-1α Immunoreactivity

Abstract: Levels of immunoreactive β‐amyloid precursor protein and interleukin‐1α were found to be elevated in surgically resected human temporal lobe tissue from patients with intractable epilepsy compared with postmortem tissue from neurologically unaffected patients (controls). In tissue from epileptics, the levels of the 135‐kDa β‐amyloid precursor protein isoform were elevated to fourfold (p < 0.05) those of controls and those of the 130‐kDa isoform to threefold (p < 0.05), whereas those of the 120‐kDa isoform (p > 0.05) were not different from control values. β‐Amyloid precursor protein‐immunoreactive neurons were 16 times more numerous, and their cytoplasm and proximal processes were more intensely immunoreactive in tissue sections from epileptics than controls (133 ± 12 vs. 8 ± 3/mm2; p < 0.001). However, neither β‐amyloid precursor protein‐immunoreactive dystrophic neurites nor β‐amyloid deposits were found in this tissue. Interleukin‐1α‐immunoreactive cells (microglia) were three times more numerous in epileptics than in controls (80 ± 8 vs. 25 ± 5/mm2; p < 0.001), and these cells were often found adjacent to β‐amyloid precursor protein‐immunoreactive neuronal cell bodies. Our findings, together with functions established in vitro for interleukin‐1, suggest that increased expression of this protein contributes to the increased levels of β‐amyloid precursor protein in epileptics, thus indicating a potential role for both of these proteins in the neuronal dysfunctions, e.g., hyperexcitability, characteristic of epilepsy.