title: Exenatide promotes cognitive enhancement and positive brain metabolic changes in PS1-KI mice but has no effects in 3xTg-AD animals.
abstract: Recent studies have shown that type 2 diabetes mellitus (T2DM) is a risk factor for cognitive dysfunction or dementia. Insulin resistance is often associated with T2DM and can induce defective insulin signaling in the central nervous system as well as increase the risk of cognitive impairment in the elderly. Glucagone like peptide-1 (GLP-1) is an incretin hormone and, like GLP-1 analogs, stimulates insulin secretion and has been employed in the treatment of T2DM. GLP-1 and GLP-1 analogs also enhance synaptic plasticity and counteract cognitive deficits in mouse models of neuronal dysfunction and/or degeneration. In this study, we investigated the potential neuroprotective effects of long-term treatment with exenatide, a GLP-1 analog, in two animal models of neuronal dysfunction: the PS1-KI and 3xTg-AD mice. We found that exenatide promoted beneficial effects on short- and long-term memory performances in PS1-KI but not in 3xTg-AD animals. In PS1-KI mice, the drug increased brain lactate dehydrogenase activity leading to a net increase in lactate levels, while no effects were observed on mitochondrial respiration. On the contrary, exenatide had no effects on brain metabolism of 3xTg-AD mice. In summary, our data indicate that exenatide improves cognition in PS1-KI mice, an effect likely driven by increasing the brain anaerobic glycolysis rate.
authors: Molecular Neurology Unit, Center of Excellence on Aging (CeSI), University Gd Annunzio Chieti-Pescara, Chieti, Italy.
authors: M
authors: M
authors: Bomba
authors: D
authors: D
authors: Ciavardelli
authors: E
authors: E
authors: Silvestri
authors: L M T
authors: LM
authors: Canzoniero
authors: R
authors: R
authors: Lattanzio
authors: P
authors: P
authors: Chiappini
authors: M
authors: M
authors: Piantelli
authors: C
authors: C
authors: Di Ilio
authors: A
authors: A
authors: Consoli
authors: S L
authors: SL
authors: Sensi
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D000077270:Exenatide; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D057567:Memory, Long-Term / Q000187:drug effects; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000201:enzymology; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D014688:Venoms / Q000494:pharmacology* / Q000627:therapeutic use; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D016875:tau Proteins; D019344:Lactic Acid; D000077270:Exenatide; D007770:L-Lactate Dehydrogenase; D003576:Electron Transport Complex IV
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