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01.12.2018 | Research | Ausgabe 1/2018 Open Access

Alzheimer's Research & Therapy 1/2018

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

Zeitschrift:
Alzheimer's Research & Therapy > Ausgabe 1/2018
Autoren:
Feng-Qin Zhou, Juan Jiang, Chelsea M. Griffith, Peter R. Patrylo, Huaibin Cai, Yaping Chu, Xiao-Xin Yan
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s13195-018-0370-2) contains supplementary material, which is available to authorized users.

Abstract

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 β-amyloid (Aβ) 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 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.

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 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.

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.
Zusatzmaterial
Additional file 1: Figure S1. Sortilin immunolabeling with the C-terminal antibody in a frontal lobe section of an aged rhesus monkey at the level of the anterior end of the striatum (St), as indicated. Figure S2. β-Amyloid (Aβ) immunolabeling with the monoclonal 6E10 antibody in a frontal lobe section of an aged rhesus monkey at the level of the anterior end of the striatum (St), as indicated. Figure S3. β-Secretase (BACE1) immunolabeling with a well-characterized rabbit antibody in a frontal lobe section of an aged rhesus monkey at the level of the anterior end of the striatum (St). Figure S4. Pattern of labeling revealed with the PHF1 monoclonal phosphorylated tau antibody in a frontal lobe section of an aged rhesus monkey at the level of the anterior end of the striatum (St). Figure S5. Sortilin immunolabeling with the C-terminal antibody in a temporal lobe section of an aged cynomolgus monkey at the level passing the anterior hippocampus and the lateral geniculate nucleus (LGN). Figure S6. β-Amyloid (Aβ) immunolabeling with the monoclonal 6E10 antibody in a temporal lobe section of an aged cynomolgus monkey at the level of the anterior hippocampus. Extracellular amyloid plaques are present in a greater amount in the medial and lateral parts of the parietal neocortex (PC) and temporal neocortex (TC), relative to the entorhinal cortex (Ent). Figure S7. β-Secretase (BACE1) immunolabeling across the hemispheric section from an aged rhesus monkey passing the lateral geniculate nucleus (LGN) and anterior hippocampus. Neuropil-like reactivity is present over the cortical gray matter. Figure S8. Non-edge-montaged Motic microscopic image covering the area of the entire hemispherical section from an aged cynomolgus monkey at the level passing the anterior hippocampus and the lateral geniculate nucleus (LGN). (PDF 1960 kb)
Literatur
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