Alzheimer’s Disease as an Autoimmune Disease

Abstract

AbstractBackgroundThe identification of new exploitable molecular pathogeneses (beyond the conventional amyloid hypothesis) for Alzheimer’s disease (AD) is a continuing neurotherapeutic priority, and has yielded a range of mechanistic proposals including immunopathy, gliopathy, mitochondriopathy, synaptopathy. However, as these new hypotheses emerge, they are often regarded as mutually exclusive and even in competition. Rather than unconditionally rejecting the role of amyloid‐β (Aβ) (or any other proposed mechanism), the need for a broadly‐encompassing model of AD, which harmonizes multiple divergent theories into a single unified explanation emerges as a much‐needed goal.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, new chemical entities were synthesized to probe the pathways identified by these molecular mechanism studies and to provide prototypic starting points in the development of small molecule therapeutics.ResultIn 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 ‘self’ neurons, arising from analogous electronegative surface topologies between neurons and bacteria, and rendering them similarly susceptible to membrane‐penetrating attack by antimicrobial peptides (AMPs) such as Aβ. Following this self‐attack, the resulting necrotic (but not apoptotic) 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. Based upon the hypothesis that autoimmune processes are susceptible to endogenous regulatory processes, a subsequent comprehensive screening program of small molecules normally present in human brain identified tryptophan metabolism as a regulator of brain innate immunity and a source of potential endogenous anti‐Alzheimer’s molecules capable of chemical modification into multi‐site therapeutic modulators targeting AD’s complex immunopathic‐proteopathic pathogenesis.ConclusionConceptualizing AD as a brain‐centric autoimmune disease of innate immunity (with Aβ as an immunopeptide), and identifying endogenous regulators of this autoimmunity, represents a novel comprehensive conceptualization approach to AD with therapeutic implications.