| Popis: |
Background While most Alzheimer’s disease cases are sporadic with late onset (LOAD), ~ 2% of cases are inherited, have an early onset, and are caused by mutations in Presenilins (PSEN1/2) or Amyloid-β Precursor Protein (APP) genes (familial AD, FAD). PSEN1/2 are the catalytic component of γ-secretase, a protease that generates Aβ peptides of different length from APP. Aβ peptides are the major components of amyloid plaques, a pathological lesion that characterizes AD. Analysis of mechanisms by which PSEN1/2 and APP mutations affect Aβ peptide compositions lead to the implication of the absolute or relative increase in Aβ42 levels in amyloid-β plaques formation and AD pathogenesis. The age at onset of FAD depends on the mutation and can differ by decades, suggesting a link between age at onset of dementia and the effects of distinct FAD mutations on Aβ species profiles. It is reasonable to presume that Aβ peptide compositions that initiate amyloid pathology and disease in FAD patients can also inform about disease mechanisms driving the more common LOAD cases. Methods Here, to elucidate the formation of pathogenic Aβ cocktails leading to amyloid pathology, we utilized rat knock-in models of FAD carrying the Swedish APP (Apps allele) and the PSEN1 L435F (Psen1LF allele) mutations. To accommodate the possibility of differences in pathogenicity of rodent and human Aβ, these rat models are genetically engineered to express human Aβ species as both the Swedish mutant allele and the wild-type rat allele (called Apph) have been humanized in the Aβ-coding region. Results Analysis of the 8 possible FAD mutant permutations demonstrates correlations between mutation-driven alterations in Aβ profiles and amyloid pathology, and indicates that the CNS levels of Aβ43, rather than absolute or relative increases in Aβ42, determine the onset of pathological amyloid deposition. Conclusions This study corroborates the critical pathological importance of alterations in the Aβ peptides composition, helps clarifying the molecular determinants initiating amyloid pathology, and supports therapeutic interventions targeting Aβ43 to prevent, delay, or revert AD. |
