Populations of Tau Conformers Drive Prion-like Strain Effects in Alzheimer’s Disease and Related Dementias

Abstract

Recent findings of diverse populations of prion-like conformers of misfolded tau protein expand the prion concept to Alzheimer’s disease (AD) and monogenic frontotemporal lobar degeneration (FTLD)-MAPT P301L, and suggest that distinct strains of misfolded proteins drive the phenotypes and progression rates in many neurodegenerative diseases. Notable progress in the previous decades has generated many lines of proof arguing that yeast, fungal, and mammalian prions determine heritable as well as infectious traits. The extraordinary phenotypic diversity of human prion diseases arises from structurally distinct prion strains that target, at different progression speeds, variable brain structures and cells. Although human prion research presents beneficial lessons and methods to study the mechanism of strain diversity of protein-only pathogens, the fundamental molecular mechanism by which tau conformers are formed and replicate in diverse tauopathies is still poorly understood. In this review, we summarize up to date advances in identification of diverse tau conformers through biophysical and cellular experimental paradigms, and the impact of heterogeneity of pathological tau strains on personalized structure- and strain-specific therapeutic approaches in major tauopathies.

Genome‐wide association studies identify novel loci in rapidly progressive Alzheimer's disease

“…rpAD in these two cohorts may represent biologically different AD mechanisms. Using conformation‐sensitive immunoassays and fluorescent ligands, our earlier findings indicate a major conformational diversity of Aβ42 accumulating in the neocortex, and at least three distinctly misfolded 4R Tau conformers associated with pathology‐confirmed rpAD in NPDPSC cohorts 4,17,19–21 . Additionally, we observed a higher APOE ε4 allele frequency in NPDPSC pathology‐confirmed rpAD cases, which might contribute to different biological mechanisms.…”

“…Finally, the different conformers (strains) of Aβ and misfolded tau protein interacting with distinct sets of proteins in rpAD suggest involvement of variable genetic factors. 4,[19][20][21]23,24 To understand the effect of genetic factors on rpAD, we first examined the APOE status in our study. In an AD population with NHE ancestry, the allele frequency of APOE ε4 was ≈ 40%.…”

“…These findings support the argument that rpAD is a distinct subtype of AD. Finally, the different conformers (strains) of Aβ and misfolded tau protein interacting with distinct sets of proteins in rpAD suggest involvement of variable genetic factors 4,19–21,23,24 …”

“…Recent data comparing the neuropathology of typical AD (tAD; having a relatively slow progression) to rpAD found no differentiating patterns in the morphology of neurofibrillary tangles and amyloid plaques, nor their distribution in different anatomic areas. 4 Emerging findings indicate that a unique molecular signature involving the conformational characteristics and size distribution of amyloid beta (Aβ), aggregates of misfolded 4R-Tau protein, 4,[17][18][19][20][21][22] and their interactomes 23,24 might differentiate rpAD from tAD and suggest prion-like propagation mechanism.…”

Aggregation of Disordered Proteins Associated with Neurodegeneration

“…Changes in the cellular milieu and/or mutation(s) in IDPs can disrupt normal protein functions, resulting in misfolding and aggregation/fibrillation [ 14 , 15 ]. Misfolded proteins can serve as conformational switches and/or seeds that proceed to self-propagation [ 16 , 17 , 18 , 19 ], taking on prion-like properties and causing cellular stress and damage [ 20 , 21 ]. Misfolded proteins can also cross-seed and induce other proteins to aggregate [ 22 , 23 , 24 , 25 ].…”