Importance of Immunological and Inflammatory Processes in the Pathogenesis and THERAPY of Alzheimer's Disease

Abstract

The contribution of autoimmune processes or inflammatory components in the etiology and pathogenesis of Alzheimer's disease (AD) has been suspected for many years. The presence of antigen-presenting, HLA-DR-positive and other immunoregulatory cells, components of complement, inflammatory cytokines and acute phase reactants have been established in tissue of AD neuropathology. Although these data do not confirm the immune response as a primary cause of AD, they indicate involvement of immune processes at least as a secondary or tertiary reaction to the preexisting pathogen and point out its driving-force role in AD pathogenesis. These processes may contribute to systemic immune response. Thus, experimental and clinical studies indicate impairments in both humoral and cellular immunity in an animal model of AD as well as in AD patients. On the other hand, anti-inflammatory drugs applied for the treatment of some chronic inflammatory diseases have been shown to reduce risk of AD in these patients. Therefore, it seems that anti-inflammatory drugs and other substances which can control the activity of immunocompetent cells and the level of endogenous immune response can be valuable in the treatment of AD patients.

Activation of microglia: A neuroinflammatory role for CAP37

“…The concept that inflammation is associated with and contributes to the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, is gaining considerable acceptance (McGeer et al, 1989;Frohman et al, 1991;Aisen, 1996;Veerhuis et al, 1996;Eikelenboom et al, 1998;McGeer and McGeer, 1998;Akiyama et al, 2000;Mrak and Griffin, 2001;Weggen et al, 2001). What remains equivocal is the elucidation of the underlying mechanisms and the identity of the mediators involved in initiating or regulating these processes (Goldbager et al, 1989;Breitner, 1996;Beard et al, 1998;Pasinetti, 1998;Pitchumoni and Doraiswamy, 1998;Popovic et al, 1998;Schubert et al, 1998;Yermakova et al, 1999;Cole and Ard, 2000). Recently, we localized CAP37 to the cerebral microvasculature of patients with Alzheimer's disease (Pereira et al, 1996b).…”

Autoimmune Encephalomyelitis and Uveitis Induced by T Cell Immunity to Self β-Synuclein

“…In previous work, we found that in analogy to the therapeutic effect of amyloid-␤ immunization in a mouse model of Alzheimer's disease (3), immunization with prion protein peptide reduced the PrP Sc content of a transplanted neuroblastoma (38). Moreover, recent publications have described inflammatory cells and molecules in several neurodegenerative diseases, including Parkinson's (39), Alzheimer's (40,41), and experimental prion disease (42). These findings raise the possibility that Ag-specific T or B cells might influence the natural history of these neurodegenerative diseases.…”

Macrophage Inflammatory Protein 2 Inhibits β-Amyloid Peptide (1-42)-Mediated Hippocampal Neuronal Apoptosis through Activation of Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase Signaling Pathways

“…The ␤-amyloid is a potent and direct neurotoxic agent, and it induces a cascade of cellular mechanisms, including activation of astrocytes and microglia. It is well known that reactive glial cells produce excessive excitatory amino acids such as glutamate and inflammatory cytokines, including interleukin 1, tumor necrosis factor-␣, and transforming growth factor-␤ (Popovic et al, 1998), that are proposed to play an important role in neuronal death. Moreover, recent studies have demonstrated that reactive glial cells also produce a number of chemokines (Yates et al, 2000;Giri et al, 2003).…”