GM6 Attenuates Alzheimer’s Disease Pathology in APP Mice
- 162 Downloads
Alzheimer’s disease (AD) results in the deposition of amyloid β (Aβ) peptide into amyloid fibrils and tau into neurofibrillary tangles. Regardless of whether or not these entities are a cause or consequence of the disease process, preventing their accumulation or accelerating their clearance may slow the rate of AD onset. Motoneuronotrophic factor (MNTF) is an endogenous neurotrophin that is specific for the human nervous system, and some of the observed effects of MNTF include motoneuron differentiation, maintenance, survival, and reinnervation of target muscles and organs. GM6 is a six-amino-acid component of MNTF that appears to replicate its activity spectrum. In this study, we investigated the effect of GM6 in a mouse model of AD before the development of amyloid plaques and determined how this treatment affected the accumulation of Aβ peptide and related pathologic changes (e.g., inflammation, nerve growth factor (NGF) expression, cathepsin B, and memory impairment). Application of GM6 over a 4-month period in young APP/ΔPS1 double-transgenic mice resulted in attenuation in Aβ peptide levels, reduction of inflammation and amyloid load, increased cathepsin B expression, and improved spatial orientation. In addition, treatment with GM6 increased brain NGF levels and tempered memory impairment by ∼ 50% at the highest dose. These data suggest that GM6 may modulate disease-determining pathways at an early stage to slow the histological and clinical progression of AD.
KeywordsAlzheimer’s Aβ peptide Behavior Cathepsin B Nerve growth factor
We would like to thank Winston Ko for his support of the studies.
Conceived and designed the experiments: JY, ST, CK, DK, and MSK. Performed the experiments: JY, HZ, ST, WM, and MSK. Performed data analysis: CK and MSK. Contributed reagents/materials/analysis tools: DK. Wrote and contributed to the writing of the manuscript: CK, DK, and MSK. All authors discussed the results and edited the manuscript.
This work was partially supported by grants from the National Institutes of Health (R01 ES016774-01, R21AG043718, 1P20GM109091, 2P20GM103444, and 5P30GM103342), VA Merit Award (1I01RX001450-01A1), a grant from the National Science Foundation (IIP-0903795), and an AHA SFRN (15SFDRN25710468) grant (M.S.K.). Dr. Kindy is a Senior Research Career Scientist in the VA.
Compliance with Ethical Standards
This research was approved by the IACUC of the University of South Florida, following the guidelines for the Care and Use of Laboratory Animals.
Dorothy Ko is an employee of Genervon and has interest in the company.
- 9.Chau RMW, Ren F, Huang W, Jen LS (1992) Muscle neurotrophic factors specific for anterior horn motoneurons of rat spinal cord. Recent Adv Cell Mol Biol 5:89–94Google Scholar
- 10.Zhou MH, Wu XY, Ren F, Zhao LP, Huang WQ, Yang ZY, Ren LS (1992) Effect of 22kD, 35kD molecules from skeletal muscle extract on ant. Horn motoneuron of lumbar spine in rat. Chin Sci Bull 37:1742–1745Google Scholar
- 11.Zhou MH, Yu WH, Reb F (1993) Changes in MNTF and its receptor in tongue muscle post-denervation of the hypoglossal nerve. Acta Anatomica Sin 24:391–395Google Scholar
- 12.Wang AM, Chau RMW, Chow SP, Zhang ZY, Li ZM (1995) Effects of myogenic 22 and 35kD neurotrophic factors on axonal regeneration in free peripheral autografts into rat spinal cord. Chin J Spine Spinal Cord 5:248–252Google Scholar
- 13.Chau, R.M.W. 2001. Polynucleotides encoding motoneuronotrophic factors. US Patent. #6,309,877.Google Scholar
- 14.Chau, R.M.W. 2005. Methods and use of motoneuronotrophic factors. US Patent. #6,841,531.Google Scholar
- 15.Chau, R.M.W. 2007. MNTF peptides and compositions and methods of use. US patent. #7,183,373.Google Scholar
- 17.Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, Copeland NG, Lee MK et al (2004) Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 13:159–170CrossRefGoogle Scholar
- 18.Savonenko A, Xu GM, Melnikova T, Morton JL, Gonzales V, Wong MP, Price DL, Tang F et al (2005) Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer’s disease: relationships to beta-amyloid deposition and neurotransmitter abnormalities. Neurobiol Dis 18:602–617CrossRefGoogle Scholar
- 28.Holtzman DM, Mandelkow E, Selkoe DJ (2012) Alzheimer disease in 2020. Cold Spring Harb Perspect Med 2(11). https://doi.org/10.1101/cshperspect.a011585
- 37.Zhou MH, Wu X, Chen S (1997) Distribution of MNTF1 in spinal cord and limb muscles of mice with motoneuron disease. Acta Acad Med Sin 19:171–178Google Scholar
- 38.Di X, Huang W (1997) Localization and morphometric study on motoneuronotrophic factor 1 and its receptor in developing chorionic villi of human placenta. Acta Anatomica Sin 29:86–89Google Scholar
- 39.Di X, Huang WQ, Sun L (1997) Immunohistochemical localization of c-fos p53 protein & MNTF1 receptor in early human placental villi. Acta Anatomica Sin 28:404–406Google Scholar
- 43.Valko KL, Ivanova-Berndt G, Beswick P, Kindy M, Ko D (2018) Application of biomimetic HPLC to estimate lipophilicity, protein and phospholipid binding of potential peptide therapeutics. ADMET & DMPK 6:153–161Google Scholar