Prions, prionoids and pathogenic proteins in Alzheimer disease

Abstract

Like patients with prion disease, Alzheimer patients suffer from a fatal, progressive form of dementia. There is growing evidence that amyloid-β (Aβ) aggregates may be transmissible similar to prions, at least under extreme experimental conditions. However, unlike mice infected with prion protein (PrP) prions, those inoculated with Aβ do not die. The transmission of Aβ and PrP thus differs conspicuously in the neurological effects they induce in their hosts, the difference being no less than a matter of life and death. Far from being a mere academic nuance, this distinction between Aβ and PrP begs the crucial questions of what, exactly, controls prion toxicity and how prion toxicity relates to prion infectivity.

Keywords: Alzheimer’s disease; PrP; amyloid-β; pathogenic proteins; prionoids; prions; tau.

Figure 1. Prions, prionoids and pathogenic proteins in neurodegenerative diseases. PrP^Sc is considered to be the transmissible agent of the prion causing scrapie, Creutzfeldt-Jakob disease and related spongiform encephalopathies. Nucleating fibrillar protein aggregates (“prionoids”) are found in many neurodegenerative diseases. With the exception of PrP^Sc, there is little evidence in mice or humans linking prionoids in the brain to the pathophysiological processes that cause the disorders connected with these proteins. Instead, accumulating data indicate that the brain dysfunction and neurological signs associated with these illnesses are caused by non-fibrillar variants of the parent proteins (*proteins). In the case of Aβ, brain dysfunction in mice and CSF tau abnormalities in humans are strongly associated with a soluble 56-kDa assembly, Aβ*. The existence of other Aβ* molecules has not been excluded. The *proteins need not be misfolded in the sense of adopting novel secondary structure, which invariably involves β-sheets. PolyQ/ataxin-1 is the best example. Distinguishing between prionoids and *proteins, and understanding how *proteins cause neurological illness, will advance our progress in treating these profoundly devastating and fatal disorders.

Figure 2. The cellular prion protein is absolutely required for the toxicity of infectious prions (A), implying that PrP^Sc exerts neurotoxicity by docking to PrP^C (B). This toxicity may also be elicited by PrP variants occurring naturally, such as PrP carrying supernumerary octapeptide repeats (C), or experimentally constructed toxic variants such as PrP versions carrying deletions of the hinge region (D). It was recently discovered that prion infection results in a chain of events that ultimately quenches protein translation, but it remains to be seen whether the toxicity elicited by PrP mutants (Panels C and D) utilizes the same pathway.