Complement in Alzheimer’s disease: opportunities for modulating protective and pathogenic events

Abstract

The complement system is a critical element of the innate immune system recognizing and killing, or targeting for destruction, otherwise pathogenic organisms. In addition to triggering the generation of a membranolytic complex, complement proteins interact with cell surface receptors to promote a local inflammatory response that contributes to the protection and healing of the host. Compelling evidence has been reported that in Alzheimer’s Disease complement activation occurs in the brain, and that this contributes to the development of a local inflammatory state that is correlated with cognitive dysfunction. However, recent data suggest that at least some of the complement components have the ability to contribute to neuroprotective pathways. Thus, it is the balance of these seemingly competing events that influences the ultimate state of neuronal function. Knowledge of the unique molecular interactions that occur in the development of Alzheimer’s Disease, the functional consequences of those interactions, and the proportional contribution of each element to this disorder, should facilitate the design of effective therapeutic strategies for this disease.

Introduction

Alzheimer’s Disease is a disorder that clinically is manifest in specific cognitive dysfunctions and is predominantly associated with aging. In the United States there are estimates of greater than 4 million afflicted individuals and, given the aging of the population, this number is predicted to increase dramatically in the future as more individuals move into the age group where the disease prevalence is highest (i.e. >65 years of age). The neuropathological structures detected upon post mortem autopsy include senile plaques and neurofibrillary tangles [108] which along with neuronal loss are the hallmark of Alzheimer’s disease (AD). Clearly, it is the loss of neurons and thus synaptic function that is the proximal cause of dementia. However, the events initiating and propagating this neuronal degeneration are as yet unknown and thus under intense investigation.

It is now clear that there can be diverse genetic or acquired events which can initiate pathways to this disease, and there is a plethora of observations suggesting multiple factors contributing to the progression of AD [24], [29], [100]. For example, some cases of AD occur in younger individuals relative to the larger number of cases of “sporadic” AD. These “early onset” AD cases have been associated with genetic mutations that result in increased production of an apparent pathogenic peptide designated β-amyloid (Aβ), which is derived from amyloid precursor protein (APP), a relatively ubiquitous protein with higher expression seen in neurons. The use of anti-β-amyloid antibodies have demonstrated that Aβ is a major protein component of the plaques seen in AD brabin [62], [99]. These plaques can be categorized according to both the pattern of β-amyloid deposits (diffuse vs fibrillar/dense-core) and, with the additional use of PHF-1 antibodies to identify neuritic structures, the absence or presence of dystrophic neurites (nonneuritic vs neuritic) [44]. It is the plaques containing fibrillar amyloid (fAβ) that are associated with clinical dementia [23]. These plaques can be stained with Congo Red and thioflavine, indicating the β-sheet secondary structure of the peptides. While it is not known what conditions in vivo are responsible for the transition to β-sheet, it does correlates with the formation of peptide fibrils which are relatively resistant to proteolysis. These thioflavine positive amyloid plaques are also associated with microglia, the macrophage of the brain, and astrocytes. While these cells are seen normally throughout the brain, plaque areas have a prominently greater density of these cells which additionally have a more activated or “reactive” morphology, indicative of an inflammatory response. The fact that brain tissue from elderly patients who are not demented have been shown to contain diffuse type plaques (which therefore are not associated with reactive/inflammatory glial cells), suggests that the nonfibrillar diffuse β-amyloid lacks the dominant cognition-impairing activity which evolves as a result of, or at least in parallel to, the conversion to the fibrillar, thioflavine-reactive plaques with its associated gliosis [75]. A comprehensive review published last year provided an integrated summary of the compelling evidence for a significant role of local inflammatory processes in the progression of AD pathogenesis [3]. While this paper will summarize evidence that continues to accumulate suggesting a pivotal role for complement activation and its proinflammatory consequences in the pathogenesis of AD, it is critical to be aware that no one pathway or factor is responsible for the development of this disease [57]. The goal are to understand the molecular basis of the interactions and reactions that impinge on this disease and to assess the proportional contribution of each element in order to facilitate the design of effective therapeutic strategies promoting the protective and inhibiting the detrimental processes.