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

Excerpt

In 2008, Acta Neuropathologica published a review cluster on genetically engineered animal models of neurodegenerative diseases comparing their similarities and differences to human neuropathology [8]. Although these models (and the ones generated since) recapitulate some pathological features of the human diseases, their overall pathology did not closely resemble what is typically observed in human brains. Nevertheless, these models were considered more or less useful as tools to try to understand mechanisms of specific proteinopathies. Although it remains to be clarified how the distribution of each cytopathology is regulated, it is possible to modify their distribution using specific promoters so that pathological proteins are artificially driven to selected areas or cell types in the nervous system. Importantly, it still remained to be explained how the distributions of protein inclusions are dictated by disease states in human brains. In recent years, some of these experimental modeling approaches have been expanded to exacerbate the localized inducing of lesions by cerebral or peripheral injections of preparations containing synthetic or biologically derived aggregate-inducing amyloid protein “seeds”, resulting in subsequent spread of pathological inclusions. These studies were based on the assumptions that (1) endogenous proteins can be modified to be pathological as they are endowed with a property to template themselves and polymerize to form pathological inclusions, and (2) this molecular process can progressively spread along neuronal processes and synapses, which is supposed to represent the reality of human brain. While these two different aspects are sometimes considered “prion-like”, this review cluster addresses whether such experimental approaches represent similarities, which could be grouped under a catch-all umbrella “prion” or “prion-like” and whether there is sufficient evidence from the human neuropathology counterpart to support such a unified mechanism. To avoid experimental or human bias, researcher pairs of a experimental neuroscientist and a human neuropathologist were selected to provide a balanced view of the current state of experimental versus descriptive findings in terms of explaining the distribution/spread of pathological lesions for some of the major proteins (α-synuclein, tau and Aβ) often found as inclusions in the brains of patients with neurodegenerative diseases. This binocular view hopefully provides a stereoscopic and more rigorous interpretation, but also highlights important discrepancies between the two aspects. As expected, this challenge introduced conflicting views in each pair, but we feel that in the end all participants were successful in demonstrating both similarities and differences between propagation experiments and human neuropathology together with their shortcomings as summarized below. …