Discovery of ADDL-Targeting Small Molecule Drugs for Alzheimers Disease

Abstract

Amyloid beta-derived diffusible ligands (ADDLs) comprise the neurotoxic subset of soluble Abeta(1-42) oligomers, now widely considered to be the molecular cause of memory malfunction and neurodegeneration in Alzheimer's disease (AD). We have developed a screening cascade which identifies small molecule modulators of ADDL-mediated neurotoxicity. The primary screen involves a fluorescence resonance energy transfer (FRET)-based assay which selects inhibitors of Abeta1-42 oligomer assembly. The identified hits were further characterized by assessing their ability to inhibit the assembly and binding of ADDLs to cultures of primary hippocampal neurons. This approach has led to the identification of a number of small molecules which inhibit ADDL assembly and their subsequent binding to neurons. Here we describe our small molecule discovery efforts to identify ADDL assembly blocker and ADDL binding inhibitors, and to transform validated hits into pre-clinical lead compounds.

Selective Acetyl- and Butyrylcholinesterase Inhibitors Reduce Amyloid-β Ex Vivo Activation of Peripheral Chemo-cytokines From Alzheimer’s Disease Subjects: Exploring the Cholinergic Anti-inflammatory Pathway

“…Aβ peptide found present in AD brain is considered primarily made locally [25]. Produced in soluble monomeric form, Aβ generates soluble oligomers that are believed to be the primary toxic species [5,71], which eventually create the aggregated Aβ found in brain amyloid plaques. Following the intravenous injection of synthetic Aβ small amounts have been detected in the brain of rodents [72] and primates [73], and, reciprocally, soluble systemic Aβ has been found in plasma after central administration [74]).…”

“…Aβ peptide is derived from the larger Aβ precursor protein (APP) by the action of β- and γ-secretases for the biogenesis of Aβ [3,4], which is detected normally in different cell types and tissues across evolutionary species. Aβ aggregation, in particular soluble oligomers, triggers a cascade of events that leads to neuronal dysfunction, neurodegeneration and ultimately to clinical dementia [5]. These Aβ aggregates may induce direct neurotoxic actions [6] but, additionally, may induce neurodegeneration indirectly by initiating a pro-inflammatory cascade that results in the release of inflammatory cytokines [7–9].…”

Correlation of Amyloid PET Ligand Florbetapir F 18 Binding With Aβ Aggregation and Neuritic Plaque Deposition in Postmortem Brain Tissue

“…These include β-amyloid contained in neuritic plaques, diffuse plaques, protofibrils, soluble oligomers and less structured aggregates. 29–33 While there is no precise and generally accepted definition of the various physical forms of amyloid, all may contribute to florbetapir F 18 binding. Lockhart et al reported correlations between histochemically- and autoradiographically-demonstrated morphological forms of amyloid deposition (including diffuse plaques, neuritic plaques, cored plaques and amyloid angiopathy).…”

The toxicity of β-amyloid is attenuated by interaction with its specific human scFv E3 in vitro

“…4 and 6A). The oligomeric Aβ is even 10-fold more neurotoxic than fibrils (Dahlgren et al, 2002;Look et al, 2007). However, the toxicity of Aβ to SK-N-SH cells was attenuated by co-incubation with E3 scFv.…”