Connessioni scientifiche n° 14: Sarah Basile

Mapping Amyloid-β post-translational modifications across deposits in Alzheimer’s disease: a neuropathological and functional analysis of nitration.

Alzheimer’s disease is characterized by the accumulation of amyloid-β (Aβ) deposits that differ in morphology, anatomical localization, biochemical composition, and associated inflammatory response. Although Aβ pathology is commonly described in terms of plaque burden and fibrillar aggregation, increasing evidence suggests that post-translational modifications (PTMs) may contribute to the biological heterogeneity of amyloid deposits. Among these modifications, Aβ nitration may represent a relevant molecular signature linking fibrillar aggregation, vascular amyloid pathology, and neuroinflammation.In this talk, I will present my PhD work on the distribution and functional relevance of nitrated Aβ in Alzheimer’s disease. Using human post-mortem brain tissue, we analyzed different Aβ species, including pyroglutamylated, phosphorylated, and nitrated forms, across morphologically distinct parenchymal plaques and vascular amyloid deposits. Our data show that Aβ deposits are not only structurally heterogeneous, but also biochemically distinct, with a progressive accumulation of PTMs in more complex and vascular-associated deposits. In particular, 3-nitrotyrosine-positive Aβ was strongly associated with β-sheet-rich structures and cerebral amyloid angiopathy.To investigate the functional impact of nitration, we also performed controlled in vitro nitration of pre-formed Aβ1-42 assemblies. Nitration altered Aβ aggregation properties, stabilized pre-formed fibrillar structures, and modulated microglial responses. In BV2 microglial cells, nitrated fibrils promoted and sustained an activated amoeboid phenotype without affecting cell viability, while nitration did not increase toxicity in differentiated SH-SY5Y neuronal-like cells. These findings suggest that Aβ nitration may uncouple amyloid aggregation from direct neuronal toxicity while promoting persistent microglial activation. Overall, this work supports the idea that Aβ PTMs encode functional diversity within Alzheimer’s disease pathology. Nitrated Aβ may contribute to compartment-specific molecular signatures, particularly in vascular amyloid pathology, and could represent a potential biomarker of cerebral amyloid angiopathy and inflammatory risk in the context of anti-amyloid therapeutic strategies.