Lack of human-like extracellular sortilin neuropathology in transgenic Alzheimer's disease model mice and macaques

Background: Alzheimer's disease (AD) is a devastating neurodegenerative disorder bearing multiple pathological hallmarks suggestive of complex cellular/molecular interplay during pathogenesis. Transgenic mice and nonhuman primates are used as disease models for mechanistic and translational research into AD; the extent to which these animal models recapitulate AD-type neuropathology is an issue of importance. Putative C-terminal fragments from sortilin, a member of the vacuolar protein sorting 10 protein (Vps10p) family, have recently been shown to deposit in the neuritic beta-amyloid (A beta) plaques in the human brain. Methods: We set out to explore if extracellular sortilin neuropathology exists in AD-related transgenic mice and nonhuman primates. Brains from different transgenic strains and ages developed overt cerebral A beta deposition, including the beta-amyloid precursor protein and presenilin 1 double-transgenic (APP/PS1) mice at similar to 14 months of age, the five familial Alzheimer's disease mutations transgenic (5xFAD) mice at similar to 8 months, the triple-transgenic Alzheimer's disease (3xTg-AD) mice at similar to 22 months, and aged monkeys (Macaca mulatta and Macaca fascicularis) were examined. Brain samples from young transgenic mice, middle-aged/aged monkeys, and AD humans were used as negative and positive pathological controls. Results: The C-terminal sortilin antibody, which labeled senile plaques in the AD human cerebral sections, did not display extracellular immunolabeling in the transgenic mouse or aged monkey brain sections with A beta deposition. In Western blot analysis, sortilin fragments similar to 15 kDa were not detectable in transgenic mouse cortical lysates, but they occurred in control AD lysates. Conclusions: In reference to their human brain counterparts, neuritic plaques seen in transgenic AD model mouse brains represent an incomplete form of this AD pathological hallmark. The species difference in neuritic plaque constituents also indicates more complex secondary proteopathies in the human brain relative to rodents and nonhuman primates during aging and in AD.