Age-Related Decrease in Glucagon-Like Peptide-1 in Mouse Prefrontal Cortex but Not in Hippocampus Despite the Preservation of Its Receptor
American Journal of BioScience
Volume 3, Issue 1, January 2015, Pages: 11-27
Received: Jan. 5, 2015;
Accepted: Jan. 20, 2015;
Published: Jan. 30, 2015
Views 2518 Downloads 151
Ryo Ohshima, Department of Pharmacology, School of Pharmaceutical Science, Ohu University, 31-1 Misumido, Tomitamachi, Koriyama, Fukushima, Japan
Kanae Hotsumi, Department of Pharmacology, School of Pharmaceutical Science, Ohu University, 31-1 Misumido, Tomitamachi, Koriyama, Fukushima, Japan
Christian Holscher, Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK
Kenjiro Seki, Department of Pharmacology, School of Pharmaceutical Science, Ohu University, 31-1 Misumido, Tomitamachi, Koriyama, Fukushima, Japan
Glucagon-like peptide-1 receptor (GLP-1R) agonist treatment has the potential to be a novel therapeutic treatment for Alzheimer’s disease (AD). We previously reported that exendin-4, a Gαs protein-coupled GLP-1R agonist, up-regulates the membrane AMPA receptor GluR1 subunit in the neocortex. However, it is uncertain whether GLP-1R agonists have an advantage as an AD treatment target compared with other Gαs protein-coupled receptors. Here we show that both the protein level of proglucagon, a precursor of GLP-1, and the immunoreactivity level of GLP-1 are significantly decreased in the medial prefrontal cortex (mPFC) of aged mice (14 months old) compared with young (3 weeks old) or adult (6 months old) mice, but not in area CA1, the dentate gyrus (DG) nor in the nucleus of the solitary tract. However, the protein and immunoreactivity levels of GLP-1R in the mPFC, DG and hippocampal CA1 and CA3 areas were preserved in the aged mice. We then confirmed whether the age-dependent decrease in GLP-1 in the mPFC was associated with the activity level or the number of microglial cells in the mPFC. Co-staining of CD11b and GLP-1 in the mPFC revealed that the number of CD11b-positive cells was increased in the aged mice. Moreover, lipopolysaccharide (LPS) injection increased the number of CD11b-positive cells in the mPFC, but the number of GLP-1-positive cells was unchanged. However, the number of CD11b-positive cells that co-localized with GLP-1R in the mPFC is increased by LPS and aging. Because the GLP-1R is preserved in aged mPFC, but the amount of GLP-1 produced in the brain region is diminished, and spatial cognitive memory was impaired in aged mice, we propose that treatment with GLP-1 analogues has great promise for rescuing and ameliorating the age-related mPFC-dependent decline of cognitive functions.
Age-Related Decrease in Glucagon-Like Peptide-1 in Mouse Prefrontal Cortex but Not in Hippocampus Despite the Preservation of Its Receptor, American Journal of BioScience.
Vol. 3, No. 1,
2015, pp. 11-27.
de la Monte SM. Brain insulin resistance and deficiency as therapeutic targets in Alzheimer's disease. Current Alzheimer research 2012; 9:35-66.
Holscher C. Diabetes as a risk factor for Alzheimer's disease: insulin signalling impairment in the brain as an alternative model of Alzheimer's disease. Biochemical Society transactions 2011; 39:891-7.
Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, et al. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. The Journal of clinical investigation 2012; 122:1316-38.
de la Monte SM. Contributions of brain insulin resistance and deficiency in amyloid-related neurodegeneration in Alzheimer's disease. Drugs 2012; 72:49-66.
Freiherr J, Hallschmid M, Frey WH, 2nd, Brunner YF, Chapman CD, Holscher C, et al. Intranasal insulin as a treatment for Alzheimer's disease: a review of basic research and clinical evidence. CNS drugs 2013; 27:505-14.
Yang Y, Zhang J, Ma D, Zhang M, Hu S, Shao S, et al. Subcutaneous administration of liraglutide ameliorates Alzheimer-associated tau hyperphosphorylation in rats with type 2 diabetes. Journal of Alzheimer's disease: JAD 2013; 37:637-48.
Femminella GD, Edison P. Evaluation of neuroprotective effect of glucagon-like peptide 1 analogs using neuroimaging. Alzheimer's & dementia: the journal of the Alzheimer's Association 2014; 10:S55-61.
Holscher C. Potential role of glucagon-like peptide-1 (GLP-1) in neuroprotection. CNS drugs 2012; 26:871-82.
Kosaraju J, Murthy V, Khatwal RB, Dubala A, Chinni S, Muthureddy Nataraj SK, et al. Vildagliptin: an anti-diabetes agent ameliorates cognitive deficits and pathology observed in streptozotocin-induced Alzheimer's disease. The Journal of pharmacy and pharmacology 2013; 65:1773-84.
Mossello E, Ballini E, Boncinelli M, Monami M, Lonetto G, Mello AM, et al. Glucagon-like peptide-1, diabetes, and cognitive decline: possible pathophysiological links and therapeutic opportunities. Experimental diabetes research 2011; 2011:281674.
Holscher C. Incretin analogues that have been developed to treat type 2 diabetes hold promise as a novel treatment strategy for Alzheimer's disease. Recent patents on CNS drug discovery 2010; 5:109-17.
Holscher C. The incretin hormones glucagonlike peptide 1 and glucose-dependent insulinotropic polypeptide are neuroprotective in mouse models of Alzheimer's disease. Alzheimer's & dementia: the journal of the Alzheimer's Association 2014; 10:S47-54.
Talbot K. Brain insulin resistance in Alzheimer's disease and its potential treatment with GLP-1 analogs. Neurodegenerative disease management 2014; 4:31-40.
Ohtake N, Saito M, Eto M, Seki K. Exendin-4 promotes the membrane trafficking of the AMPA receptor GluR1 subunit and ADAM10 in the mouse neocortex. Regulatory peptides 2014; 190-191:1-11.
McClean PL, Gault VA, Harriott P, Holscher C. Glucagon-like peptide-1 analogues enhance synaptic plasticity in the brain: a link between diabetes and Alzheimer's disease. European journal of pharmacology 2010; 630:158-62.
McClean P, Parthsarathy V, Faivre E, Hölscher C. The diabetes drug Liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease. J Neurosci 2011; 31:6587-94.
Abbas T, Faivre E, Holscher C. Impairment of synaptic plasticity and memory formation in GLP-1 receptor KO mice: Interaction between type 2 diabetes and Alzheimer's disease. Behavioural brain research 2009; 205:265-71.
During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, et al. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nature medicine 2003; 9:1173-9.
Thathiah A, De Strooper B. The role of G protein-coupled receptors in the pathology of Alzheimer's disease. Nature reviews Neuroscience 2011; 12:73-87.
Hallbrink M, Holmqvist T, Olsson M, Ostenson CG, Efendic S, Langel U. Different domains in the third intracellular loop of the GLP-1 receptor are responsible for Galpha(s) and Galpha(i)/Galpha(o) activation. Biochimica et biophysica acta 2001; 1546:79-86.
Pimenova AA, Thathiah A, De Strooper B, Tesseur I. Regulation of amyloid precursor protein processing by serotonin signaling. PloS one 2014; 9:e87014.
Kojro E, Postina R, Buro C, Meiringer C, Gehrig-Burger K, Fahrenholz F. The neuropeptide PACAP promotes the alpha-secretase pathway for processing the Alzheimer amyloid precursor protein. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 2006;20:512-4.
Perry T, Holloway HW, Weerasuriya A, Mouton PR, Duffy K, Mattison JA, et al. Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy. Experimental neurology 2007; 203:293-301.
Dore S, Kar S, Quirion R. Insulin-like growth factor I protects and rescues hippocampal neurons against beta-amyloid- and human amylin-induced toxicity. Proceedings of the National Academy of Sciences of the United States of America 1997; 94:4772-7.
Signore AP, Zhang F, Weng Z, Gao Y, Chen J. Leptin neuroprotection in the CNS: mechanisms and therapeutic potentials. Journal of neurochemistry 2008; 106:1977-90.
Bradbury J. Hope for AD with NGF gene-therapy trial. Lancet neurology 2005; 4:335.
Nagahara AH, Merrill DA, Coppola G, Tsukada S, Schroeder BE, Shaked GM, et al. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease. Nature medicine 2009; 15:331-7.
Oh H, Madison C, Haight TJ, Markley C, Jagust WJ. Effects of age and beta-amyloid on cognitive changes in normal elderly people. Neurobiology of aging 2012; 33:2746-55.
Bakkour A, Morris JC, Wolk DA, Dickerson BC. The effects of aging and Alzheimer's disease on cerebral cortical anatomy: specificity and differential relationships with cognition. NeuroImage 2013; 76:332-44.
Puddu A, Sanguineti R, Montecucco F, Viviani GL. Retinal pigment epithelial cells express a functional receptor for glucagon-like peptide-1 (GLP-1). Mediators of inflammation 2013; 2013:975032.
Hamilton A, Holscher C. Receptors for the incretin glucagon-like peptide-1 are expressed on neurons in the central nervous system. Neuroreport 2009; 20:1161-6.
Renner E, Puskas N, Dobolyi A, Palkovits M. Glucagon-like peptide-1 of brainstem origin activates dorsomedial hypothalamic neurons in satiated rats. Peptides 2012; 35:14-22.
Gier B, Butler PC, Lai CK, Kirakossian D, DeNicola MM, Yeh MW. Glucagon like peptide-1 receptor expression in the human thyroid gland. The Journal of clinical endocrinology and metabolism 2012; 97:121-31.
Trapp S, Richards JE. The gut hormone glucagon-like peptide-1 produced in brain: is this physiologically relevant? Current opinion in pharmacology 2013; 13:964-9.
Kappe C, Tracy LM, Patrone C, Iverfeldt K, Sjoholm A. GLP-1 secretion by microglial cells and decreased CNS expression in obesity. Journal of neuroinflammation 2012; 9:276.
Iwai T, Ito S, Tanimitsu K, Udagawa S, Oka J. Glucagon-like peptide-1 inhibits LPS-induced IL-1beta production in cultured rat astrocytes. Neuroscience research 2006; 55:352-60.
Merchenthaler I, Lane M, Shughrue P. Distribution of pre-pro-glucagon and glucagon-like peptide-1 receptor messenger RNAs in the rat central nervous system. The Journal of comparative neurology 1999; 403:261-80.
Norden DM, Godbout JP. Review: microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathology and applied neurobiology 2013; 39:19-34.
Hart AD, Wyttenbach A, Perry VH, Teeling JL. Age related changes in microglial phenotype vary between CNS regions: grey versus white matter differences. Brain, behavior, and immunity 2012; 26:754-65.
Cao L, Wang F, Yang QG, Jiang W, Wang C, Chen YP, et al. Reduced thyroid hormones with increased hippocampal SNAP-25 and Munc18-1 might involve cognitive impairment during aging. Behavioural brain research 2012; 229:131-7.
Nichol KE, Parachikova AI, Cotman CW. Three weeks of running wheel exposure improves cognitive performance in the aged Tg2576 mouse. Behavioural brain research 2007;184:124-32.
Murphy GG, Rahnama NP, Silva AJ. Investigation of age-related cognitive decline using mice as a model system: behavioral correlates. The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry 2006; 14:1004-11.
Carrie I, Debray M, Bourre JM, Frances H. Age-induced cognitive alterations in OF1 mice. Physiology & behavior 1999; 66:651-6.
Stoll S, Hafner U, Pohl O, Muller WE. Age-related memory decline and longevity under treatment with selegiline. Life sciences 1994; 55:2155-63.
Jo YS, Park EH, Kim IH, Park SK, Kim H, Kim HT, et al. The medial prefrontal cortex is involved in spatial memory retrieval under partial-cue conditions. J Neurosci 2007; 27:13567-78.
Magnusson KR, Scruggs B, Zhao X, Hammersmark R. Age-related declines in a two-day reference memory task are associated with changes in NMDA receptor subunits in mice. BMC neuroscience 2007; 8:43.
Bordner KA, Kitchen RR, Carlyle B, George ED, Mahajan MC, Mane SM, et al. Parallel declines in cognition, motivation, and locomotion in aging mice: association with immune gene upregulation in the medial prefrontal cortex. Experimental gerontology 2011; 46:643-59.
Enns LC, Morton JF, Mangalindan RS, McKnight GS, Schwartz MW, Kaeberlein MR, et al. Attenuation of age-related metabolic dysfunction in mice with a targeted disruption of the Cbeta subunit of protein kinase A. The journals of gerontology Series A, Biological sciences and medical sciences 2009; 64:1221-31.
Morris JK, Vidoni ED, Honea RA, Burns JM. Impaired glycemia increases disease progression in mild cognitive impairment. Neurobiology of aging 2014; 35:585-9.
Cabou C, Campistron G, Marsollier N, Leloup C, Cruciani-Guglielmacci C, Penicaud L, et al. Brain glucagon-like peptide-1 regulates arterial blood flow, heart rate, and insulin sensitivity. Diabetes 2008; 57:2577-87.
Cabou C, Vachoux C, Campistron G, Drucker DJ, Burcelin R. Brain GLP-1 signaling regulates femoral artery blood flow and insulin sensitivity through hypothalamic PKC-delta. Diabetes 2011; 60:2245-56.
Long-Smith CM, Manning S, McClean PL, Coakley MF, O'Halloran DJ, Holscher C, et al. The diabetes drug liraglutide ameliorates aberrant insulin receptor localisation and signalling in parallel with decreasing both amyloid-beta plaque and glial pathology in a mouse model of Alzheimer's disease. Neuromolecular medicine 2013; 15:102-14.
Bomfim TR, Forny-Germano L, Sathler LB, Brito-Moreira J, Houzel JC, Decker H, et al. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Abeta oligomers. The Journal of clinical investigation 2012; 122:1339-53.
Perry VH, Matyszak MK, Fearn S. Altered antigen expression of microglia in the aged rodent CNS. Glia 1993; 7:60-7.
Henry CJ, Huang Y, Wynne AM, Godbout JP. Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1beta and anti-inflammatory IL-10 cytokines. Brain, behavior, and immunity 2009; 23:309-17.
Morgan TE, Xie Z, Goldsmith S, Yoshida T, Lanzrein AS, Stone D, et al. The mosaic of brain glial hyperactivity during normal ageing and its attenuation by food restriction. Neuroscience 1999; 89:687-99.
Yi CX, Tschop MH, Woods SC, Hofmann SM. High-fat-diet exposure induces IgG accumulation in hypothalamic microglia. Disease models & mechanisms 2012; 5:686-90.
Fan R, Tenner AJ. Differential regulation of Abeta42-induced neuronal C1q synthesis and microglial activation. Journal of neuroinflammation 2005; 2:1.
Kappe C, Zhang Q, Holst JJ, Nystrom T, Sjoholm A. Evidence for paracrine/autocrine regulation of GLP-1-producing cells. American journal of physiology Cell physiology 2013; 305:C1041-9.
Li Y, Duffy KB, Ottinger MA, Ray B, Bailey JA, Holloway HW, et al. GLP-1 receptor stimulation reduces amyloid-beta peptide accumulation and cytotoxicity in cellular and animal models of Alzheimer's disease. Journal of Alzheimer's disease: JAD 2010; 19:1205-19.
Scali C, Prosperi C, Bracco L, Piccini C, Baronti R, Ginestroni A, et al. Neutrophils CD11b and fibroblasts PGE(2) are elevated in Alzheimer's disease. Neurobiology of aging 2002; 23:523-30.
Yan Q, Zhang J, Liu H, Babu-Khan S, Vassar R, Biere AL, et al. Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer's disease. J Neurosci 2003; 23:7504-9.
van Groen T, Miettinen P, Kadish I. Transgenic AD model mice, effects of potential anti-AD treatments on inflammation, and pathology. Journal of Alzheimer's disease: JAD 2011; 24:301-13.
Jimenez S, Baglietto-Vargas D, Caballero C, Moreno-Gonzalez I, Torres M, Sanchez-Varo R, et al. Inflammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer's disease: age-dependent switch in the microglial phenotype from alternative to classic. J Neurosci 2008; 28:11650-61.
Schacter DL, Savage CR, Alpert NM, Rauch SL, Albert MS. The role of hippocampus and frontal cortex in age-related memory changes: a PET study. Neuroreport 1996; 7:1165-9.
Morrison JH, Baxter MG. The ageing cortical synapse: hallmarks and implications for cognitive decline. Nature reviews Neuroscience 2012; 13:240-50.
Araki T, Wake R, Miyaoka T, Kawakami K, Nagahama M, Furuya M, et al. The effects of combine treatment of memantine and donepezil on Alzheimer's Disease patients and its relationship with cerebral blood flow in the prefrontal area. International journal of geriatric psychiatry 2014.
Holscher C. The incretin hormones glucagonlike peptide 1 and glucose-dependent insulinotropic polypeptide are neuroprotective in mouse models of Alzheimer's disease. Alzheimer's & dementia: the journal of the Alzheimer's Association 2014; 10:S47-S54.
Tripathy D, Sanchez A, Yin X, Martinez J, Grammas P. Age-related decrease in cerebrovascular-derived neuroprotective proteins: effect of acetaminophen. Microvascular research 2012; 84:278-85.
Kastin AJ, Akerstrom V. Entry of exendin-4 into brain is rapid but may be limited at high doses. International journal of obesity and related metabolic disorders: journal of the International Association for the Study of Obesity 2003; 27:313-8.
Hunter K, Holscher C. Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC neuroscience 2012;13:33-8.
Holscher C. Insulin, incretins and other growth factors as potential novel treatments for Alzheimer's and Parkinson's diseases. Biochemical Society transactions 2014;42:593-9.
McClean PL, Parthsarathy V, Faivre E, Holscher C. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease. J Neurosci 2011; 31:6587-94.
McClean PL, Holscher C. Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer's disease. Neuropharmacology 2014; 76 Pt A:57-67.