N‐ and C‐Terminal Alzheimer’s Aβ Heterogeneity Modulates the Balance Between Brain Clearance and Amyloid Formation

Impaired brain clearance and abnormal Aβ degradation are today considered key events for the formation and progressive accumulation of soluble neurotoxic oligomers and the development of synaptic pathology, one of the strongest correlates to cognitive impairment in Alzheimer’s disease (AD). Clearance studies, mostly centered in monomeric Aβ40, have provided a basic assessment of the participating mechanisms, but the complex molecular and structural heterogeneity of the brain Aβ peptidome –going far beyond the classic Aβ40/Aβ42 dichotomy–has been largely overlooked. The most common heterogeneity resides in the multiple truncated fragments that consistently populate the Aβ peptidome and of which little is known in regard to their homeostatic regulation and potential contribution to disease pathogenesis. Tissue specimens from AD cases and transgenic models subjected to differential solubility extractions followed by immunoprecipitation coupled to mass spectrometry revealed the extent and characteristics of the multiple N‐ and C‐terminal truncated Aβ species. The data indicate that C‐terminal truncations increase Aβ solubility and abrogate oligomerization and fibrillogenesis, features clearly associated with clearance mechanisms, whereas N‐terminal truncations, particularly abundant components of parenchymal and vascular amyloid deposits in AD, non‐human primates, and multiple APP transgenic models drive enhanced pro‐amyloidogenic properties. Biophysical studies using synthetic homologues confirmed the differences in solubility further illustrating the contrasting oligomerization/fibrillization characteristics of the various Aβ truncated derivatives, and novel antibodies recognizing specific N‐ and C‐terminal truncations differentially immunolabeled amyloid deposits in AD brains and transgenic models. Intracerebral injections of monomeric and oligomeric radiolabeled homologues revealed striking differences in their brain clearance characteristics, showing that while soluble derivatives exhibited a fast brain removal, oligomerization largely increased brain retention, a characteristic particularly evident in fragments truncated at Phe4, topographically abundant in fibrillar, thioflavin positive plaque cores. Overall, our data indicate that degradation at the C‐terminus generates highly soluble Aβ fragments that are common components of interstitial and cerebrospinal fluids, and likely associated to catabolic/clearance mechanisms whereas truncations at the N‐terminus favor oligomerization and brain retention, with the potential to exacerbate the process of amyloid formation and self‐perpetuate the amyloidogenic loop. Support or Funding Information NIH grants AG059595 and AG051266, and the BrightFocus Foundation grant A2015275S