Review article
Inflammatory processes in Alzheimer's disease

https://doi.org/10.1016/j.jneuroim.2006.11.017Get rights and content

Abstract

Generation and deposition of amyloid beta peptides and neurofibrillary tangle formation are key mechanisms involved in AD pathogenesis. Recent evidence suggests that inflammatory mechanisms represent a third component which, once initiated by degeneration, may significantly contribute to disease progression and chronicity. Various neuroinflammatory mediators including complement activators and inhibitors, chemokines, cytokines, radical oxygen species and inflammatory enzymes are generated and released by microglia, astrocytes and neurons. Degeneration of aminergic brain stem nuclei such as the locus ceruleus and the nucleus baslis of Meynert may facilitate the occurrence of inflammation in their respective projection areas given the antiinflammatory and neuroprotective action of their key products norepinephrine and acetylcholine. While inflammation has been thought to arise secondary to degeneration, recent experiments demonstrated that inflammatory mediators may stimulate APP processing by upregulation of beta secretase 1 and therefore are able to establish a vicious cycle. Despite the fact that some aspects of inflammation may even exert protective effects to bystander neurons, antiinflammatory treatment strategies should therefore be considered. Non-steroidal antiinflammatory drugs have been shown to reduce the risk and delay the onset to develop AD. However, the precise molecular mechanism underlying this effect is still being debated. Several mechanisms including inhibition of cyclooxygenase 2, gamma secretase or activation of the peroxisome proliferator activated receptor gamma may alone or, more likely, in concert account for the epidemiologically observed protection.

Section snippets

Alzheimer's disease

As the most common neurodegenerative disorders, Alzheimer's disease (AD) currently affects 20 to 30 million individuals worldwide (Selkoe, 2005). AD accounts for most cases of dementia that are diagnosed after the age of 60 years of life. In the US, the number reaches roughly 4 million patients. The prevalence of AD increases with age, affecting approximately 1% to 3% of the population in the 6th decade of life, 3% to 12% of the population between 70 and 80 years, and up to 25 to 35% older than

Inflammation and AD

Although Aβ has been considered to play a key role in AD pathogenesis (Walsh et al., 2002b, Walsh and Selkoe, 2004), it remains still uncertain whether Aβ plaques and neurofibrillary tangles are causative for AD. These doubts are fueled by the finding that the Aβ plaque burden poorly correlates with the progression and severity of dementia in AD. Moreover, transgenic animals that develop widespread Aβ plaque deposition in response to overexpression of APP mutations show only slight cognitive

Immunostimulators in Alzheimer's disease

While minor signs of neuroinflammation can be found in the normal aging brain, the AD brain faces a much stronger activation of inflammatory systems indicating that an increasing amount or qualitatively different immunostimulants are present. Cumulative evidence suggests that Aβ peptides play a pivotal role as inducers of neuroinflammation. However, chromogranin and several other proteins may contribute to this induction.

Cellular components of neuroinflammation in Alzheimer's disease

Microglia cells represent the brain innate immune system and hence the first line of defense when challenged by bacterial, viral or fungal infection. Although these functions are of major importance and beneficial, it has become clear that microglial activation may also be evoked by endogenous proteins and can significantly contribute to neuronal damage. Along with microglia, astrocytes and even neurons are directly reacting and contributing to the chronic neuroinflammatory changes in AD.

Pro- and antiinflammatory mediators

The neuroinflammatory response observed in AD is characterized by a whole array of pro- and antiinflammatory mediators including members of the complement cascade, chemo- and cytokines as well as inflammatory enzyme systems. Several of these factors may promote neurodegenerative mechanisms while others may rather limit ongoing inflammatory changes or even exert beneficial neurotrophic effects. Thus, not a single mediator but rather the entire spectrum of inflammatory agents will determine

Inflammatory cytokines

The cytokine class of inflammatory mediators is secreted by microglia and astrocytes surrounding β-amyloid neuritic plaques. Cytokines associated with AD include several interleukins (ILs), TNF-α and TGFβ along with several others. Their production is increased in inflammatory states and they function by regulating the intensity and duration of the immune response (Tuppo and Arias, 2005).

In astrocytes, IL-1 induces IL-6 production, stimulates iNOS activity (Rossi and Bianchini, 1996), and

Inflammation-permissive factors in AD

Occurrence and deposition of aggregated, misfolded or phosphorylated proteins may play the pivotal role for the induction and ongoing stimulation of inflammation in the AD brain. However, since some of these proteins may well occur in the normal aging brain without evoking such a dramatic immune response, it may be hypothesized that several other changes in AD are facilitating inflammation. Loss of aminergic brains stem nuclei, such as the locus ceruleus and the nucleus basalis of Meynert, may

Cytokine driven feedback mechanisms

Apart from self-propagation and direct cytopathic effect on neurons, cytokines may more directly contribute to AD related neurodegeneration. Thus, studies performed in transgenic animals suggest that cerebral amyloid deposition is increased under inflammatory conditions (Games et al., 1995, Guo et al., 2002). Moreover, these animals do not develop amyloid plaques unless inflammation is induced suggesting that inflammatory molecules either raise the susceptibility for Aβ deposition and

Functional and structural consequences of neuroinflammation in AD

Over the past decade, numerous lines of evidence have strongly suggested that neuroinflammation contributes to AD pathogenesis. Irregardless at which time point of the disease it occurs, it seems clear that once initiated, inflammatory pathomechanisms can affect the AD brain. Functional and structural consequences may be differentiated to understand the various levels at which inflammation may contribute to AD.

Antiinflammatory treatment strategies

Neuroinflammatory changes may even occur at early stages in the AD brain and significantly contribute to the pathogenesis of the disease. This raises the question whether therapeutic strategies can be developed which successfully target the ongoing inflammation.

Conclusions and future directions

Increasing evidence suggests that inflammation significantly contributes to the pathogenesis of AD. The generation and secretion of proinflammatory mediators may interact at multiple levels with neurodegenerative mechanisms. Thus, several proinflammatory cytokines cannot only induce neuropathic mechanisms and thereby contribute to neuronal death, but are also able to influence classical neurodegenerative pathways such as APP processing. The concomitant release of antiinflammatory mediators may

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