1 research outputs found
Alzheimer's disease as an autoimmune disorder of innate immunity endogenously modulated by tryptophan metabolites
Abstract Introduction Alzheimer's disease (AD) is characterized by neurotoxic immunoâinflammation concomitant with cytotoxic oligomerization of amyloid beta (Aβ) and tau, culminating in concurrent, interdependent immunopathic and proteopathic pathogeneses. Methods We performed a comprehensive series of in silico, in vitro, and in vivo studies explicitly evaluating the atomisticâmolecular mechanisms of cytokineâmediated and Aβâmediated neurotoxicities in AD. Next, 471 new chemical entities were designed and synthesized to probe the pathways identified by these molecular mechanism studies and to provide prototypic starting points in the development of smallâmolecule therapeutics for AD.  Results In response to various stimuli (e.g., infection, trauma, ischemia, air pollution, depression), Aβ is released as an early responder immunopeptide triggering an innate immunity cascade in which Aβ exhibits both immunomodulatory and antimicrobial properties (whether bacteria are present, or not), resulting in a misdirected attack upon âselfâ neurons, arising from analogous electronegative surface topologies between neurons and bacteria, and rendering them similarly susceptible to membraneâpenetrating attack by antimicrobial peptides (AMPs) such as Aβ. After this selfâattack, the resulting necrotic (but not apoptotic) neuronal breakdown products diffuse to adjacent neurons eliciting further release of Aβ, leading to a chronic selfâperpetuating autoimmune cycle. AD thus emerges as a brainâcentric autoimmune disorder of innate immunity. Based upon the hypothesis that autoimmune processes are susceptible to endogenous regulatory processes, a subsequent comprehensive screening program of 1137 small molecules normally present in human brain identified tryptophan metabolism as a regulator of brain innate immunity and a source of potential endogenous antiâAD molecules capable of chemical modification into multiâsite therapeutic modulators targeting AD's complex immunopathicâproteopathic pathogenesis. Discussion  Conceptualizing AD as an autoimmune disease, identifying endogenous regulators of this autoimmunity, and designing small molecule drugâlike analogues of these endogenous regulators represents a novel therapeutic approach for AD