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Lack of human-like extracellular sortilin neuropathology in transgenic Alzheimer's disease model mice and macaques.
Alzheimers Res Ther. 2018 04 24; 10(1):40.AR

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.

Authors+Show Affiliations

Department of Anatomy and Neurobiology, Central South University School of Basic Medical Science, Changsha, 410013, Hunan, China.Department of Anatomy and Neurobiology, Central South University School of Basic Medical Science, Changsha, 410013, Hunan, China.Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL, 62901, USA.Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL, 62901, USA.Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, 60612, USA.Department of Anatomy and Neurobiology, Central South University School of Basic Medical Science, Changsha, 410013, Hunan, China. yanxiaoxin@csu.edu.cn. Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, Hunan, China. yanxiaoxin@csu.edu.cn.

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29690919

Citation

Zhou, Feng-Qin, et al. "Lack of Human-like Extracellular Sortilin Neuropathology in Transgenic Alzheimer's Disease Model Mice and Macaques." Alzheimer's Research & Therapy, vol. 10, no. 1, 2018, p. 40.
Zhou FQ, Jiang J, Griffith CM, et al. Lack of human-like extracellular sortilin neuropathology in transgenic Alzheimer's disease model mice and macaques. Alzheimers Res Ther. 2018;10(1):40.
Zhou, F. Q., Jiang, J., Griffith, C. M., Patrylo, P. R., Cai, H., Chu, Y., & Yan, X. X. (2018). Lack of human-like extracellular sortilin neuropathology in transgenic Alzheimer's disease model mice and macaques. Alzheimer's Research & Therapy, 10(1), 40. https://doi.org/10.1186/s13195-018-0370-2
Zhou FQ, et al. Lack of Human-like Extracellular Sortilin Neuropathology in Transgenic Alzheimer's Disease Model Mice and Macaques. Alzheimers Res Ther. 2018 04 24;10(1):40. PubMed PMID: 29690919.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lack of human-like extracellular sortilin neuropathology in transgenic Alzheimer's disease model mice and macaques. AU - Zhou,Feng-Qin, AU - Jiang,Juan, AU - Griffith,Chelsea M, AU - Patrylo,Peter R, AU - Cai,Huaibin, AU - Chu,Yaping, AU - Yan,Xiao-Xin, Y1 - 2018/04/24/ PY - 2017/12/11/received PY - 2018/03/19/accepted PY - 2018/4/26/entrez PY - 2018/4/25/pubmed PY - 2019/8/28/medline KW - Brain aging KW - Dementia KW - Neurodegenerative diseases KW - Vps10p KW - β-Amyloid SP - 40 EP - 40 JF - Alzheimer's research & therapy JO - Alzheimers Res Ther VL - 10 IS - 1 N2 - 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. SN - 1758-9193 UR - https://www.unboundmedicine.com/medline/citation/29690919/Lack_of_human_like_extracellular_sortilin_neuropathology_in_transgenic_Alzheimer's_disease_model_mice_and_macaques_ L2 - https://alzres.biomedcentral.com/articles/10.1186/s13195-018-0370-2 DB - PRIME DP - Unbound Medicine ER -