Mechanisms of Microglial Activation by Amyloid Precursor Protein and its Proteolytic Fragments
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease (Selkoe, 2005). Histologically, it is characterized by the deposition of extracellular senile plaques composed primarily of beta amyloid (Aβ) peptides and intracellular inclusions, termed neurofibrillary tangles, made up of primarily hyperphosphorylated tau protein (Braak and Braak, 1997a, b; Grundke-Iqbal et al., 1986; Selkoe, 2001). In addition, AD brains demonstrate significant neuron loss and abundant gliosis (McGeer et al., 1986). The mechanisms by which these pathology occur, however, is debatable. It has been hypothesized that inflammatory events contribute to both the histological and behavioral progression of disease (Akiyama et al., 2000). The histological data demonstrating gliotic changes in AD brains as compared to agematched controls certainly supports the notion that microglia, in particular, may mediate the changes that are observed. Reactive microglia with swollen bodies and shortened, thickened processes are histologically identified in close association with the fibrillar or congophilic plaques in the AD brain (Itagaki et al., 1989; Miyazono et al., 1991). Although the percentage of microglia associated with fibrillar plaques is greater, they are also localized, in a more ramified phenotype, with the diffuse plaques (Itagaki et al., 1989; Mattiace et al., 1990; Sasaki et al., 1997). These data suggest that microglia develop a specific reactive phenotype in association with plaques as Aβ undergoes a transition from a nonfibrillar to fibrillar, congophilic conformation (Sheng et al., 1997). In fact, some studies suggest that microglia are involved in the earliest stages of plaque deposition perhaps even dictating where plaques are depositing in the brain (Griffin et al., 1995; Sheng et al., 1995, 1998). Moreover, AD brains have increased protein levels of several proinflammatory mediators commonly associated with reactive microgliosis, including cytokines: interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, activated complement components, and cyclooxygenase (COX)-2 when compared to controls (Akiyama et al., 2000; Dickson et al., 1993; Eikelenboom et al., 1989; Luterman et al., 2000; Mrak and Griffin, 2000; O'Banion et al., 1997; Strauss et al., 1992; Xiang et al., 2006;). Strikingly similar observations have been made while examining transgenic mouse models of disease over the last decade. The majority of the mouse models that have been created over-express human mutant forms of the amyloid precursor protein (APP) and/or mutant forms of the proteins responsible for gamma secretase cleavage of APP, presenilin (PS) 1 and PS2. These animal models have consistently demonstrated that reactive microgliosis occurs in association with fibrillar plaque formation as detected histologically with multiple immuno-markers (Morgan et al., 2005). Collectively, a voluminous body of data strengthens the proposition that APP and its proteolytic fragments are involved in not just plaque deposition but also the reactive microgliosis observed in AD brains.
KeywordsPlaque Deposition Neurobiol Aging Mitogen Activate Protein Kinase Activity Amyloid Protein Precursor Gene Amyloid Cascade Hypothesis
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