Lih-Fen Lue

Inflammation and Alzheimer's disease pathogenesis

Appreciation of the role that inflammatory mediators play in Alzheimers disease (AD) pathogenesis continues to be hampered by two related misconceptions. The first is that to be pathogenically significant a neurodegenerative mechanism must be primary. The second is that inflammation merely occurs to clear the detritis of already existent pathology. The present review addresses these issues by showing that 1) inflammatory molecules and mechanisms are uniquely present or significantly elevated in the AD brain, 2) inflammation may be a necessary component of AD pathogenesis, 3) inflammation may be sufficient to cause AD neurodegeneration, and 4) retrospective and direct clinical trials suggest a therapeutic benefit of conventional antiinflammatory medications in slowing the progress or even delaying the onset of AD.

Molecular and Cellular Characterization of the Membrane Attack Complex, C5b-9, in Alzheimer’s Disease

The membrane attack complex, C5b-9, is of considerable importance in many inflammatory reactions. It is the terminal, cytolytic component of both classical and alternative pathway activation, and its presence presupposes other potentially destructive complement constituents, including anaphylotoxins and opsonins. We have characterized C5b-9 and its C9 constituent in the Alzheimers disease (AD) and nondemented elderly (ND) brain using immunohistochemistry at the light and electron microscopic levels, Western blot analysis, and the reverse transcriptase polymerase chain reaction. We have also conducted in vitro ELISA assays of amyloid beta-peptide-stimulated SC5b-9 production. C5b-9 is abundantly present in Alzheimers disease cortex, associated with neurofibrillary tangle containing neurons, dystrophic neurites within neuritic plaques, and neuropil threads, but is weakly detected, if at all, in nondemented elderly cortex under the same conditions. Staining of Alzheimers disease sections is abolished both by deletion of primary antibody or preabsorption with purified SC5b-9.

The involvement of glial cell-derived reactive oxygen and nitrogen species in Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by adult-onset progressive dementia and mainly affects the elderly. Pathologically, the brains of AD patients are characterized by the presence of neurofibrillary tangles (NFTs), amyloid β peptide (Aβ)-containing senile plaques (SPs) and synaptic and neuronal cell loss. Most research on AD has focused on the mechanisms that result in the formation of these insoluble NFTs and SPs [1 2]. NFTs represent the insoluble filamentous remnants of the cytoskeleton of affected neurons, with a major component being phosphorylated forms of the microtubule-associated protein tau. SPs primarily contain aggregated Aβ peptide fragments derived from the amyloid precursor protein (APP). In AD brains, both SPs and NFTs, as well as vulnerable neurons, have been shown to undergo a number of modifications indicative of ongoing oxidative stress [3-12].

Microglial Responses in Alzheimer’s Disease

This chapter will consider the significance of a range of markers used in studies to describe activated microglia and reactive astrocytes in chronic neurodegenerative disorders, particularly as they are modeled in the recently developed transgenic mice models of Alzheimer’s disease (AD). The purpose of this chapter is to discuss the significance of these markers in describing the degenerative mechanisms that are progressing in this disease or models of this disease. Since the completion of the first article dealing with this topic (1), there have been a number of major publications concerning the presence of inflammatory microglia and astrocyte markers in transgenic mice models of AD. These mice develop AD-like amyloid β peptide (Aβ) plaques as a result of the possession of mutated copies of the amyloid precursor protein (APP) genes (2–6). A comparison of the expression of inflammatory markers in these AD models with those expressed in AD brain tissues will be included in this chapter. Significant progress in understanding the appearance of inflammatory markers in these Aβ plaque-developing animals has come from the fact that they can be sacrificed and studied at different time-points during the development of the plaques. This type of study is obviously not possible in human patients. In addition, these animals allow one to study the effects of progressive deposition of Aβ independent of other events proceeding in an aging human brain.