Research Article: Lack of human-like extracellular sortilin neuropathology in transgenic Alzheimer’s disease model mice and macaques

Date Published: April 24, 2018

Publisher: BioMed Central

Author(s): Feng-Qin Zhou, Juan Jiang, Chelsea M. Griffith, Peter R. Patrylo, Huaibin Cai, Yaping Chu, Xiao-Xin Yan.


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 β-amyloid (Aβ) plaques in the human brain.

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 Aβ deposition, including the β-amyloid precursor protein and presenilin 1 double-transgenic (APP/PS1) mice at ~ 14 months of age, the five familial Alzheimer’s disease mutations transgenic (5×FAD) mice at ~ 8 months, the triple-transgenic Alzheimer’s disease (3×Tg-AD) mice at ~ 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.

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 Aβ deposition. In Western blot analysis, sortilin fragments ~ 15 kDa were not detectable in transgenic mouse cortical lysates, but they occurred in control AD lysates.

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.

The online version of this article (10.1186/s13195-018-0370-2) contains supplementary material, which is available to authorized users.

Partial Text

Many transgenic mouse lines are produced as animal models of Alzheimer’s disease (AD), with the majority being engineered to overexpress mutant β-amyloid precursor protein (APP) and/or presenilin 1 or 2 (PS1, PS2) genes identified from patients with early-onset familial AD (FAD) [1–3]. The commonly studied mouse lines include mice overexpressing the APPSwed transgenes (Tg2576) [4], APP/PS1 double-transgenic mice (2×FAD) [5], and mice with five FAD-linked APP/PS1 mutations (5×FAD) [6], all developing β-amyloid (Aβ) deposition in the brain with age. The triple-transgenic mouse model of AD (3×Tg-AD) also harbors a mutant human tau (P301L) gene associated with frontotemporal dementia [7] and develops both plaque- and tangle-like pathologies in the brain [8]. Transgenic AD models are widely used in exploratory studies and have provided insights into the biological, pathogenic, and behavioral/cognitive underpinnings of this disease [2, 3, 9, 10]. These animal models have also served as a prime system for the development and evaluation of various AD therapeutic approaches [1, 11, 12]. However, though in many cases excellent pharmacological efficacy is established in preclinical experiments with transgenic AD models, no effective medicine has been translated to patients to date, owing to repeated failure at various stages of clinical drug trails. This has led to discussions on the extent to which the transgenic models have sufficiently recapitulated the complexity of human AD pathology [13–17].

The scientific community has experienced great difficulty developing effective AD therapy despite decades’ worth of efforts. As failed drug trials are repeatedly announced, concerns arise as to whether the molecular drug target(s), the model system(s) used in preclinical tests, or the designs of clinical trials (e.g., beginning trials on predemented vs. demented patient cohorts) are sufficiently suited for successfully delivering mechanism-based medicine [12–17]. A further point is whether certain as yet unforeseen but functionally relevant pathologies of human AD remain to be integrated into preclinical drug-testing models to allow more predictable clinical trial outcomes. Thus, deepening the understanding of human AD pathology and pathogenesis, including exploration and validation of the inclusiveness of human-type neuropathology in animal models, remains not only important and necessary but also might extend novel cutting-edge to advance basic and translational research toward better disease diagnosis and care.

On the basis of lack of cerebral extracellular sortilin pathology in APP/PS1, 5×FAD and 3×Tg-AD mice, and aged macaques bearing overt cerebral β-amyloid deposition, we conclude that neuritic plaques of humans are constituently different relative to rodents and nonhuman primates. Specifically, neuritic amyloid plaques seen in transgenic mouse models of AD actually represent an incomplete form of this disease hallmark pathology. The human-specific extracellular sortilin pathology also implies a greater brain proteopathy in humans relative to rodents and nonhuman primates during aging and in AD.




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