| dc.description.abstracteng | Alzheimer’s disease is the most commonly occurring dementia of the elderly, comprising up to 75% of all the neurodegenerative disorders. Over the past few decades, some atypical AD cases have been reported with a higher degree of pathological severity and rapid progression rates. The present study was undertaken to identify and characterize the mechanisms involved in the progression rate variations in Alzheimer’s disease subtypes, using human frontal cerebral cortex samples from rapidly progressive AD (rpAD), sporadic (spAD), sporadic Creutzfeldt Jakob disease (sCJD), and other rapid progressive dementias.
Microscopic examination revealed a decrease in amyloid plaque diameters, with a significantly higher frequency in cortices of rpAD patients compared to spAD. Signaling pathways were assessed by expression analyses of a battery of kinases and a slight increase in the CaMKII subunit gamma was observed in spAD in comparison to both controls and rpAD cases. Differential metabolism of prion protein (PrP) was studied in Alzheimer’s subtypes, for its involvement in Aβ oligomer sequestering. A significant decrease was noted in the di-glycosylated isoform of prion protein (DG-PrP) in rpAD cases, along with a decrease in the extracellular PrP levels. The reduction in the levels of both DG-PrP and extracellular PrP can be linked to the disturbance in the amyloid-sequestering activity of prion protein and a consequent higher load of free toxic oligomers. Subtype-specific differences among PrP interactomes were also observed, with histone-2 B2 and ZAG specifically interacting with prion protein in rpAD frontal cortices, suggesting the presence of differential prion variants in Alzheimer subtypes. PK-sensitive high-density variants of prion proteins (HDP) were uniquely observed in the rpAD frontal cortices, along with rpAD-specific higher load of proteopathic proteins, disturbances in the protein degradation machinery, cytoskeletal disfigurations, and relative abundance of chaperones. An rpAD-unique HDP interactor, GAS2-like protein 2 (G2L2) was also identified. The G2L2 serves as a linker protein between the tubulin bundles and actin filaments to stabilize the microtubules via attachment to end binding protein-1. A significantly more pronounced colocalization of G2L2 and PrP was seen in the frontal cortex tissues of rapidly progressive AD cases, with an associated decrease in the colocalization of G2L2 and end binding protein-1 (EB-1). A decrease in the actin-β and tubulin-α co-localization was also noted in frontal cortex tissues of AD cases with rapid progression.
Based on the results, we confirm that prion protein metabolism plays an important role in the progression rate of Alzheimer’s disease. The dysregulation of PrP maturation leads to impairment of oligomer sequestration. Formation of PrP oligomers and their downstream intervention with cell signaling and cytoskeletal organization promotes the faster progression in rapidly progressive Alzheimer’ disease cases. | de |