Review article
Inflammatory processes in Alzheimer's disease

https://doi.org/10.1016/S0278-5846(03)00124-6Get rights and content

Abstract

Neuroinflammation is a characteristic of pathologically affected tissue in several neurodegenerative disorders. These changes are particularly observed in affected brain areas of Alzheimer's disease (AD) cases. They include an accumulation of large numbers of activated microglia and astrocytes as well as small numbers of T-cells, mostly adhering to postcapillary venules. Accompanying biochemical alterations include the appearance or up-regulation of numerous molecules characteristic of inflammation and free radical attack. Particularly important may be the complement proteins, acute phase reactants and inflammatory cytokines. These brain phenomena combined with epidemiological evidence of a protective effect of antiinflammatory agents suggest that such agents may have a role to play in treating the disease.

Introduction

Alzheimer's disease (AD) is the major form of dementia, affecting roughly 1% of people at age 65 and approximately doubling in incidence for every additional 5 years of age. Most cases are sporadic, but 5–10% show a familial association linked to several genes or genetic loci. Other genes, notably apolipoprotein E (apoE) and some of the inflammatory cytokines, are believed to influence the risk of “sporadic” AD. The causes of AD are unknown and it is now considered that it may be of heterogeneous origin, with various etiologies leading to the characteristic plaque and tangle pathology.

AD tissue is characterized by neuroinflammatory changes, which are observed in both sporadic and familial AD as well as in some other forms of dementia such as in the Parkinson dementia complex of Guam or in Pick's disease. The chronic inflammation is not causative, although it may greatly influence the pathogenesis, in which case there may be potential for antiinflammatory therapy. There have been numerous exhaustive reviews recently published on inflammatory changes in AD brain (e.g., Neuroinflammation Working Group, 2000), and in this paper, we will only touch on some aspects that appear to offer therapeutic opportunities.

The concept of neuroinflammation has undergone a major transformation in recent years. Classically, it had been equated with a prominent invasion of the brain by leukocytes (Haymaker and Adams, 1982). Such an invasion occurs in all types of CNS infection, in presumed autoimmune diseases such as multiple sclerosis and in injuries or strokes where the blood–brain barrier is breached. However, this restricted view has failed to take into account landmark discoveries of the past. It was Metchnikoff (1892) who first provided insight into the localized nature of inflammation. He impaled starfish larvae with rose thorns and noticed mesenchymal cells, which he named phagocytes, gathering around the site of injury. He concluded that inflammation was primarily a local phenomenon and that dolor, tumor, rubor and calor, the cardinal signs of Celsus, were a secondary reaction caused by exudation of blood-borne elements into tissue. Del Rio Hortega (1919) identified microglia as the phagocytes of brain and established that they were of mesenchymal origin. Van Furth (1982) provided closure with his description of the monocyte phagocytic system. He showed that all tissue-based phagocytes were originally derived from monocytes and that they migrated into tissues to provide a first line of defense.

These concepts, particularly with regard to the origin and function of microglia, were regarded with considerable skepticism until recent years (Davis and Robertson, 1991), when more sophisticated molecular biological techniques became available. Now that the in vivo and in vitro properties of microglia have been more appropriately examined McGeer and McGeer, 1995, Neuroinflammation Working Group, 2000, it is generally recognized that their activation signifies a primary inflammatory state and that leukocyte invasion, when it occurs, is a secondary phenomenon.

Section snippets

Cellular evidence

The key cellular event signaling the presence of neuroinflammation in AD is the accumulation of reactive microglia in the degenerating areas. Significant activation of microglia appears to occur in a very early stage of the disease before severe cognitive decline has occurred (Vehmas et al., 2003). Clumps of activated microglia appear on the senile plaques and many others are evident in surrounding tissue Luber-Narod and Rogers, 1988, McGeer et al., 1988. Fig. 1 illustrates this phenomenon.

Biochemical evidence: oxidative stress, neurotoxins and types of compounds involved

Inflammation generates oxidative stress. It has long been suspected that oxidative stress contributes to the lesions of AD, but the presence of oxygen free radicals has usually been attributed to accidental leakage from the electron transport chain of mitochondria. However, the most abundant source of oxygen free radicals in the CNS is the respiratory burst system of activated microglia. When the system is turned on, large numbers of superoxide ions are generated on the microglial external

Complement proteins

A prominent part of the inflammatory reaction in AD is activation of the classical complement pathway. Complement is a sophisticated attack system designed to destroy invaders and to assist in the phagocytosis of waste materials. The complement system (Quigg, 2002) has components to carry out four major functions: recognition, opsonization, inflammatory stimulation through anaphylatoxins and direct killing through the membrane attack complex (MAC). The classical pathway is activated by

The pentraxins

The pentraxins may be important activators of the complement system in AD brain Jiang et al., 1992, Hicks et al., 1992 since both are found extensively in affected regions. It had been generally believed for many years that CRP and AP were produced in the liver and carried in the circulation to other organs. The presence of AP in the brain in AD was even taken as an indication of leakage in the blood–brain barrier (Kalaria and Grahovac, 1990). Application of molecular genetic techniques has

Cytokines

Cytokines are a heterogeneous group of small molecules that act in autocrine and paracrine fashion. They encompass several subfamilies, which include interleukins (ILs), INFs, tumor necrosis factors (TNFs), growth factors, colony stimulating factors and chemokines. They have in common participation in inflammatory reactions. They typically act in combination so that attributing a specific set of in vivo properties to any given cytokine is difficult.

Only a few of the cytokines have been

Possible use of antiinflammatories as therapeutic agents

The inflammatory reaction in AD could represent nothing more than an epiphenomenon in which detritus, secondary to an unrelated degenerative phenomenon, is being scavenged. However, the increases in complement mRNAs, which are observed in sporadic AD, are more robust than those observed in other pathological situations, such as rheumatoid arthritis (Fig. 4), where active inflammation is established. Thus, while clearing of dedritus must occur as the disease proceeds, the evidence favors the

Conclusions

There is now overwhelming evidence that a state of chronic inflammation exists in affected regions of AD brain. The presence of high concentrations of the MAC of complement in affected neurites suggests that this inflammation is contributing to the progressive neuronal death characteristic of the disorder. Epidemiological data suggest that traditional NSAIDs may slow the onset and progression of the disease if used at an early enough stage.

Other types of antiinflammatory agents may be equally

Acknowledgements

This work was supported by the Jack Brown and Family Alzheimer's Disease Research Fund and grants from the Alzheimer Society of Canada/CIHR/Astra-Zeneca.

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