Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer’s disease

Abstract

The molecular architecture of amyloids formed in vivo can be interrogated using luminescent conjugated oligothiophenes (LCOs), a unique class of amyloid dyes. When bound to amyloid, LCOs yield fluorescence emission spectra that reflect the 3D structure of the protein aggregates. Given that synthetic amyloid-β peptide (Aβ) has been shown to adopt distinct structural conformations with different biological activities, we asked whether Aβ can assume structurally and functionally distinct conformations within the brain. To this end, we analyzed the LCO-stained cores of β-amyloid plaques in postmortem tissue sections from frontal, temporal, and occipital neocortices in 40 cases of familial Alzheimer's disease (AD) or sporadic (idiopathic) AD (sAD). The spectral attributes of LCO-bound plaques varied markedly in the brain, but the mean spectral properties of the amyloid cores were generally similar in all three cortical regions of individual patients. Remarkably, the LCO amyloid spectra differed significantly among some of the familial and sAD subtypes, and between typical patients with sAD and those with posterior cortical atrophy AD. Neither the amount of Aβ nor its protease resistance correlated with LCO spectral properties. LCO spectral amyloid phenotypes could be partially conveyed to Aβ plaques induced by experimental transmission in a mouse model. These findings indicate that polymorphic Aβ-amyloid deposits within the brain cluster as clouds of conformational variants in different AD cases. Heterogeneity in the molecular architecture of pathogenic Aβ among individuals and in etiologically distinct subtypes of AD justifies further studies to assess putative links between Aβ conformation and clinical phenotype.

Amyloid fibril polymorphism: a challenge for molecular imaging and therapy

“…Spectroscopic changes of the LCO fluorescence response correlated in vitro with concomitant formation of bundled fibrils by AFM and TEM. A recent study of Aβ polymorphism in human samples using the same technology revealed a distribution of spectroscopic signatures from Aβ plaque cores . This strongly suggests that a cloud‐like diversity of Aβ conformations exists within each patient, representative of the variations of Aβ fibrils within a single sample .…”

“…This strongly suggests that a cloud‐like diversity of Aβ conformations exists within each patient, representative of the variations of Aβ fibrils within a single sample . The conformational cloud was weighted towards a certain type of mature or immature fibril distributions depending on the predisposing mutations in the PS1 and APP genes for fAD cases . However, it is not directly known what causes these variations in the qFTAA staining properties; that is, whether they are influenced, for example, by covalent modifications or the presence of nonfibril amyloid plaque components that account for different architectures of the biological deposit .…”

“…A major challenge for drug development is to target shape‐shifting polymorphic MPs. As individual patients display a distribution of MP polymorphs observed as microscopic morphotypes, a particular clinical disease progression, as recently shown for AD (Fig. ), was suggested to be dominated by various polymorphs that propagate efficiently .…”

Prion-like mechanisms in Alzheimer disease

“…An important indication that variant CJD (the human prionosis that is linked to bovine spongiform encephalopathy) is caused by a novel prion strain was the discovery of atypical lesions termed florid plaques in affected humans (Ironside et al, 2000). As in the case of PrP-prions, Aβ can fold into strain-like variants both in vitro (Petkova et al, 2005; Nilsson et al, 2007; Yagi et al, 2007; Paravastu et al, 2008; Meinhardt et al, 2009; Miller et al, 2010; Kodali et al, 2010; Agopian and Guo, 2012; Spirig et al, 2014; Tycko, 2015; Tycko, 2016) and in vivo (Meyer-Luehmann et al, 2006; Rosen et al, 2010; Rosen et al, 2011; Lu et al, 2013; Heilbronner et al, 2013; Watts et al, 2014; Stohr et al, 2014; Cohen et al, 2015; Condello et al, 2018; Rasmussen et al, 2017). Cerebral Aβ assemblies in humans with AD vary in terms of plaque morphology (Wisniewski et al, 1989; Thal et al, 2006), ligand binding characteristics (Rosen et al, 2010; Condello et al, 2018; Rasmussen et al, 2017), solid-state nuclear magnetic resonance features (Qiang et al, 2017), as well as conformational stability and other biophysical characteristics (Cohen et al, 2015).…”

“…Cerebral Aβ assemblies in humans with AD vary in terms of plaque morphology (Wisniewski et al, 1989; Thal et al, 2006), ligand binding characteristics (Rosen et al, 2010; Condello et al, 2018; Rasmussen et al, 2017), solid-state nuclear magnetic resonance features (Qiang et al, 2017), as well as conformational stability and other biophysical characteristics (Cohen et al, 2015). Interestingly, Aβ extracted from the autopsied brains of nondemented elderly subjects exhibits molecular-level features that differ in some ways from AD-derived Aβ (Piccini et al, 2005; Portelius et al, 2015).…”