Propagation of Aß pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies

Abstract

In brains of patients with Alzheimer's disease (AD), Aβ peptides accumulate in parenchyma and, almost invariably, also in the vascular walls. Although Aβ aggregation is, by definition, present in AD, its impact is only incompletely understood. It occurs in a stereotypical spatiotemporal distribution within neuronal networks in the course of the disease. This suggests a role for synaptic connections in propagating Aβ pathology, and possibly of axonal transport in an antero- or retrograde way-although, there is also evidence for passive, extracellular diffusion. Striking, in AD, is the conjunction of tau and Aβ pathology. Tau pathology in the cell body of neurons precedes Aβ deposition in their synaptic endings in several circuits such as the entorhino-dentate, cortico-striatal or subiculo-mammillary connections. However, genetic evidence suggests that Aβ accumulation is the first step in AD pathogenesis. To model the complexity and consequences of Aβ aggregation in vivo, various transgenic (tg) rodents have been generated. In rodents tg for the human Aβ precursor protein, focal injections of preformed Aβ aggregates can induce Aβ deposits in the vicinity of the injection site, and over time in more distant regions of the brain. This suggests that Aβ shares with α-synuclein, tau and other proteins the property to misfold and aggregate homotypic molecules. We propose to group those proteins under the term "propagons". Propagons may lack the infectivity of prions. We review findings from neuropathological examinations of human brains in different stages of AD and from studies in rodent models of Aβ aggregation and discuss putative mechanisms underlying the initiation and spread of Aβ pathology.

Propagation of Aβ, tau and α-synuclein pathology between experimental models and human reality: prions, propagons and propaganda

“…In contrast with α-synuclein, tau pathology in Alzheimer's disease (AD) predominantly spreads in the anterograde direction as seen in the dentate gyrus, even if experimental studies demonstrated the possibility of either anterograde or retrograde spread [2,4]. As pointed out by Lewis and Dickson in this issue [4], it is not yet clear whether such anterograde spread is shared with other tau-related diseases such as progressive supranuclear palsy, corticobasal degeneration, or Pick´s disease.…”

“…Even though hierarchical distribution as formulated by Thal and CERAD staging are current frameworks for Aβ spread [2], their underlying mechanisms are poorly explained. As described in the review by Eisele and Duyckaerts in this issue [2], experimental studies have provided compelling evidence that brain inoculations of "seeds" of aggregated Aβ can induce the further aggregation of endogenous Aβ, which is mechanistically much more straightforward given the extracellular nature of Aβ peptides. Nevertheless, these studies have not yet provided a clear picture of the predominant mechanism involved in the more restricted spread of Aβ pathology that may include intraneuronal, extraneuronal, and perivascular routes.…”

“…This impression could be exaggerated to the extent that potential infectivity of these pathological proteins across individuals is overemphasized, which attracted public attention to "propagation", potentially serving as a propaganda in favor of the protagonist researchers. To avoid such confusion, Eisele and Duyckaerts used and expanded the term "propagon" just to describe "what is being propagated or which specific aspect has been investigated" [2]. For example, this terminology can be coupled with specific descriptive terms such as "molecular propagon" or "tissue propagon".…”

Transmission interhumaine des protéinopathies du système nerveux central : les données disponibles en 2016

“…Si les concepts mécanistiques et infectieux sont bien associés dans le cas des maladies à prions, il semble clair que cela ne vaut pas dans tout phénomène biologique où ces modifications conformationnelles sont observées. Cette dernière décennie, un ensemble cohérent de données suggère que les assemblages de protéines mal conformées impliquées dans nombre de maladies neurodégénératives puissent se comporter comme des prions dans différentes modalités expérimentales (pour revue voir (Goedert, 2015) et (Walker & Jucker, 2015)) faisant naitre un certain nombre de néologismes tel que « prion-like », « prionoids », « propagons » ou encore « pseudoprions » pour qualifier ces structures moléculaires et leur comportement (Aguzzi, 2009;Ayers et al, 2016;Eisele & Duyckaerts, 2016). Ceci reflète la difficulté, en pathologie humaine, à utiliser le terme de prion qui fait implicitement craindre la possibilité d'une transmission interhumaine de certaines maladies neurodégénératives.…”

Genetic risk factors of Alzheimer's disease and cell-to-cell transmission of Tau

“…Multiple other proteins associated with neurodegenerative diseases, including amyloid-β peptide (Aβ), α-synuclein, mutant SOD1, mutant huntingtin and TDP-43, have also been shown to propagate protein misfolding pathology between cells in a similar prionlike manner, although the respective neuropathological cascades may vary in the human brain (reviewed in 9,10 ). How the accumulation and spreading of Aβ and Tau aggregates are mechanistically connected in human AD brain remains largely a mystery 11 . Clearly, however, Tau pathology can develop and spread in the absence of Aβ plaques, as evidenced by numerous tauopathies, such as familial cases of frontotemporal dementia that are primarily driven by aggregation-promoting mutations in the MAPT gene (that encodes the Tau protein) 12 .…”