Focal Inflammation in the Brain: Role in Alzheimer's Disease

Abstract

We hypothesize that amyloid (Abeta) peptide-containing neuritic plaques in the brains of patients with Alzheimer's disease represent chronic inflammatory foci mediated by the actions of the complement system and proinflammatory cytokines. In support of this, in vitro studies show that the (Abeta) peptide is a potent complement activator and that such complement activation leads to the formation of covalent (Abeta)-C3 activation fragment complexes, the generation of the chemokine-like C5a complement activation peptide, and the formation of the proinflammatory C5b-9 complex in functionally active form able to insert into neuronal cell membranes. Other studies show that C5a, together with (Abeta), synergistically augments the release of proinflammatory cytokines from human monocytes. These studies, which provide in vitro support for the hypothesis, are being pursued in an animal model of Alzheimer's disease.

Identification of a Potent and Orally Active Non-peptide C5a Receptor Antagonist

“…C5a exerts these activities by binding to G-protein-coupled C5a receptor (C5aR) 1 on the plasma membrane of target cells (3). These biological activities of C5a are implicated in a variety of diseases such as rheumatoid arthritis (4,5), systemic lupus erythematosus (6 -9), reperfusion injury (10), Alzheimer's disease (11)(12)(13)(14)(15), and sepsis (16,17). The pathogenic action of C5/C5a is also shown in some animal models.…”

Inflammatory changes parallel the early stages of Alzheimer disease

“…Cognitive dysfunction in AD may also be critically influenced by Aβ-induced brain inflammation [3,13,37,41,61]. Specifically, Aβ accumulation leads to a site-specific activation of glia resulting in the secretion of pro-inflammatory cytokines [3,13].…”

“…Specifically, Aβ accumulation leads to a site-specific activation of glia resulting in the secretion of pro-inflammatory cytokines [3,13]. The inflammatory response may be an attempt to clear Aβ deposits; however, the progressive accumulation of Aβ and its aggregation into insoluble plaques may induce a chronic pro-inflammatory response leading to compromised neuronal function [8].…”

Influence of Reduced Nicotinamide Adenine Dinucleotide on the Production of Interleukin-6 by Peripheral Human Blood Leukocytes

“…These findings suggested a positive effect of NADH on these CNS disorders. In addition, some publications favor an additional role of the immune system in disease progression in the brain [9]. However, the role of distinct cytokine proteins in the induction or maintenance of brain inflammation and homeostasis is currently disputed [10,11].…”