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P4‐318: T3D‐959: A multi‐faceted disease remedial drug candidate for the treatment of Alzheimer's disease
Author(s) -
Didsbury John,
Monte Suzanne
Publication year - 2015
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2015.08.148
Subject(s) - ex vivo , in vivo , morris water navigation task , pharmacology , neuroprotection , medicine , neuroscience , amyloid beta , hippocampal formation , hippocampus , biology , pathology , disease , microbiology and biotechnology
of disease-modifying therapeutics. However, a major impediment to progress may lie in fundamental differences between humans and animal model species, largely rodents. Disruption of hippocampal insulin signaling has recently been described in the brains of AD patients and animal models of disease, which could contribute to cognitive impairment in this disease. Therefore, drugs that can restore normal insulin function in the central nervous system have been recently suggested as a promising novel approach to treat AD. Methods:Here, we evaluated the neuroprotective effects of liraglutide in cynomolgus macaques (Macaca fascicularis) that received intracerebroventricular injections of Ab oligomers (AbOs). Liraglutide is an anti-diabetic agent that activates pathways common to insulin signaling through stimulation of glucagon-like peptide 1 (GLP-1) receptors. Nine female cynomolgus macaques were used. Three of them were sham-operated and served as controls. We performed intracerebroventricular (i.c.v.) injections of AbOs into six cynomolgus macaques. Two of these monkeys had been pre-treated with daily i.p. injections of liraglutide. Liraglutide administration continued daily until the last injection of oligomers. Brain sections were used for immunohistochemystry to evaluate the levels of synaptic markers. Results:We found that AbOs induced a decrease in synapse number in the primate brain and reduced the levels of NMDA (GluN1 and GluN2B subunits), AMPA (GluA1 and GluA2 subunits) and insulin receptors. Liraglutide attenuated the impact of AbOs on synapses and on plasticity related receptors. Conclusions: These results establish the protective actions of liraglutide in the primate brain and indicates that a primate model of AD may be valuable not only for studying mechanisms responsible for AbOs toxicity, but also for exploring and evaluating new preventive therapeutic strategies for AD.