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.

Pyruvate prevents the development of age-dependent cognitive deficits in a mouse model of Alzheimer's disease without reducing amyloid and tau pathology

“…In contrast, the H subunit, encoded by the LDHB gene, converts lactate to pyruvate that is further oxidized. Forward (LDH Pyr-Lac ) and reverse (LDH Lac-Pyr ) LDH activities were assayed spectrophotrometrically as previously described (Bomba et al, 2013). Briefly, treated (n = 3) and untreated (n = 3) brain tissues were homogenized in phosphate buffer solution (20 mL/g of tissue, 0.010 M, pH = 7.4).…”

“…Briefly, cytosolic brain homogenates (50 μL) were treated as previously described (Bomba et al, 2013) and GC-MS analysis performed using a 6890 N gas-chromatograph equipped with a 7863 Series auto-sampler and coupled with a 5973 N mass spectrometer (Agilent Technologies) operating in electron impact ionization mode. Injection was performed in pulsed-splitless mode by applying a pressure of 80 psi.…”

Glucagon-like peptide-1 regulates mitochondrial biogenesis and tau phosphorylation against advanced glycation end product-induced neuronal insult: Studies in vivo and in vitro

“…Bomba et al pointed that exenatide had different effects on cognitive performances in two AD transgenic mouse models: the PS1-KI mouse and the 3xTg-AD mouse. The positive cognitive effects were observed in exenatide-treated PS1-KI mice but not in 3xTg-AD mice (Bomba et al, 2013). The study of Bomba et al is very novel because they confirmed exenatide may act as a cognitive enhancer and suggested exenatide was not so effective in 3xTg-AD mice, that more closely mimic the human disease.…”

Application of APP/PS1 Transgenic Mouse Model for Alzheimer’s Disease

“…mutant, the APP KI mutation alone does not affect markers for adult hippocampal neurogenesis [12]. PS1 KI mice, a model that shows cognitive decline developed in an Aβ-independent way, therefore plaque-dependent pathology cannot be expected [13].…”

“…mutant, the APP KI mutation alone does not affect markers for adult hippocampal neurogenesis [12]. PS1 KI mice, a model that shows cognitive decline developed in an Aβ-independent way, therefore plaque-dependent pathology cannot be expected [13].Tg models are important models for the AD study. They are established on the basis of genetics, mainly involves amyloid precursor protein(APP) gene on chromosome 21, presenilin1 (PS1) gene on chromosome 14, presenilin 2 (PS2) gene on chromosome 1, Tau protein gene on chromosome 17 and Apolipoprotein E (ApoE) gene on chromosome 19 [14].…”