Design, Synthesis and Biological Assessment of Ferulic Acid Derivatives as Inhibitors of β-Amyloid Oligomerization in Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurological disorder that arises from the abnormal folding of β-amyloid (Aβ) and its subsequent aggregation. The resulting oligomers are hypothesized to be responsible for synaptic loss and neuronal cell death. Consequently, a potential therapeutic approach is to use a drug-like small molecule to bind Aβ and prevent its oligomerization, thus arresting the progression of AD. A class of small molecules that has been shown to interfere with the aberrant self-assembly of Aβ are phenolic acids. Among these, ferulic acid, a phenylalanine metabolite and potent antioxidant, was identified as an effective small molecule inhibitor of Aβ oligomerization. Herein, a library of ferulic acid derivatives was designed, synthesized and biologically evaluated for prevention or disruption of Aβ oligomerization.M.Sc.2019-01-11 00:00:0

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 immuno‐inflammation 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 atomistic–molecular mechanisms of cytokine‐mediated and Aβ‐mediated 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 small‐molecule 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 “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. After 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 1137 small molecules normally present in human brain identified tryptophan metabolism as a regulator of brain innate immunity and a source of potential endogenous anti‐AD molecules capable of chemical modification into multi‐site therapeutic modulators targeting AD's complex immunopathic–proteopathic pathogenesis.  Discussion  Conceptualizing 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