Alzheimer’s Disease as an Innate Autoimmune Disease Regulated by Tryptophan and Arginine Metabolism

Abstract

AbstractBackgroundThe identification of exploitable molecular pathogeneses for Alzheimer’s (AD) is an ongoing neurotherapeutic priority, yielding a range of different mechanistic proposals including proteopathy, immunopathy, gliopathy, synaptopathy, mitochondriopathy, oxidative stress, and metal dyshomeostasis. Rather than unconditionally accepting/rejecting the role of any one specific disease mechanism, the need for an innovative broadly‐encompassing model of AD, which harmonizes multiple divergent theories into a single unified comprehensive explanation, emerges as a much‐needed milestone on the road to a cure. Characterizing AD as a neurotoxic autoimmune‐inflammatory disorder, culminating in concurrent, interdependent immunopathic and proteopathic pathogeneses, may be such a milestone.MethodWe performed a comprehensive series of in silico, in vitro and in vivo studies explicitly evaluating the atomistic‐molecular mechanisms of cytokine‐mediated and Aβ‐mediated neurotoxicities in AD. Next, 981 new chemical entities were designed and synthesized to probe the biochemical pathways identified by these molecular mechanism studies and to provide prototypic starting points in the development of small molecule therapeutics for AD.ResultIn response to various stimuli (infection, trauma, ischemia, air pollution), 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 ‘self’ neurons, arising from analogous electronegative surface topologies between neurons and bacteria, and rendering them similarly susceptible to membrane‐penetrating attack by antimicrobial peptides such as Aβ. Following this self‐attack, the resulting necrotic neuronal breakdown products diffuse to adjacent neurons eliciting further release of Aβ, leading to a chronic self‐perpetuating autoimmune cycle. AD thus emerges as a brain‐centric autoimmune disorder of innate immunity. Since autoimmune processes are susceptible to endogenous regulatory processes, a subsequent comprehensive screening program of 1,137 small molecules normally present in human brain identified tryptophan and arginine metabolism as regulators of brain innate immunity and a source of endogenous anti‐Alzheimer’s molecules capable of modification into therapeutic modulators targeting AD’s complex immunopathic‐proteopathic pathogenesis.ConclusionConceptualizing AD as an autoimmune disease, identifying endogenous regulators of this autoimmunity, and designing small molecule drug‐like analogues of these endogenous regulators represents a novel therapeutic approach for AD.