HumanAPOEallelic variants suppress the formation of diffuse and fibrillar Aβ deposits relative to mouseApoein transgenic mouse models of Alzheimer amyloidosis

Abstract

AbstractBackgroundApolipoprotein E (apoE) modulates the deposition of amyloid β (Aβ) aggregates in Alzheimer’s disease (AD) in an isoform-dependent manner. In transgenic mouse models of AD-amyloidosis, replacing mouseApoealleles with humanAPOEvariants suppresses fibrillar Aβ deposits. In the PD-APP transgenic mouse model, deletion of theApoegene led to selective reduction of fibrillar deposits with increased diffuse deposits. This finding suggested that apoE may have differential effects on different types of amyloid pathology.MethodsHere, we investigated the interaction between the type of Aβ pathology in the brain and human apoE isoforms in different transgenic mouse models.ResultsIn the APPsi model that develops predominantly diffuse Aβ plaques late in life, we determined that replacing mouseApoewith humanAPOE3orAPOE4genes potently suppressed diffuse amyloid formation, with apoE3 exhibiting a greater activity relative to apoE4. Relative to apoE4, apoE3 appeared to suppress Aβ deposition in the cerebral vasculature. In a second cohort, we accelerated the deposition of diffuse Aβ pathology by seeding, finding that seeded APPsi mice harboringAPOE4orAPOE3developed equal burdens of diffuse parenchymal Aβ. Finally, in the recently developed SAA-APP model that has a mix of dense-core and fibrous Aβ plaques, we found that replacing mouse apoE with human apoE suppressed deposition significantly, with the amyloid burden following the trend ofApoe>>APOE4> APOE3∼APOE2. In the SAA-APP and seeded APPsi models, we found evidence of apoE protein associated with Aβ plaques.ConclusionsOverall, these observations demonstrate a capacity for human apoE to suppress the deposition of both diffuse and fibrillar-cored deposits, relative to mouse apoE. Notably, in the seeded paradigm, the suppressive activity of human apoE3 and apoE4 appeared to be overwhelmed. Taken together, this study demonstrates thatAPOEgenotype influences the deposition of both cored-fibrillar and diffuse amyloid.