Secondary Logo

Journal Logo

Glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide analogues as novel treatments for Alzheimer’s and Parkinson’s disease

Hölscher, Christian

Cardiovascular Endocrinology & Metabolism: September 2016 - Volume 5 - Issue 3 - p 93–98
doi: 10.1097/XCE.0000000000000087
Review Articles

Type 2 diabetes is a risk factor for developing chronic neurodegenerative disorders such as Alzheimer’s disease (AD) or Parkinson’s disease (PD). The underlying mechanism appears to be insulin desensitization in the brain. A range of glucagon-like peptide 1 (GLP-1) mimetics and glucose-dependent insulinotropic polypeptide (GIP) analogues initially designed to treat diabetes protected transgenic animals that model AD and toxin-based animal models of PD. Novel dual GLP-1/GIP analogues also show good neuroprotective effects. On the basis of these findings, first clinical trials have been conducted. In a pilot study on patients with AD, the GLP-1 analogue liraglutide showed good protective effects in 18F-fluorodeoxyglucose (18F-FDG)-PET brain imaging. It was found that the disease-related decay of brain activity had been completely stopped by the drug. In a pilot study in patients with PD, the GLP-1 mimetic exendin-4 showed good protection from motor and cognitive impairments. These results demonstrate the potential of developing disease-modifying treatments for AD and PD.

Division of Biomedical and Life Science, Faculty of Health and Medicine, Furness College, Lancaster University, Lancaster, UK

Correspondence to Christian Hölscher, PhD, Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Furness College, Lancaster University, B65, Lancaster LA1 4YQ, UK Tel: +44 1524 594 870; e-mail:

Received May 2, 2016

Accepted June 23, 2016

Back to Top | Article Outline

Diabetes is a risk factor for neurodegenerative disorders

One of the established risk factors for the development of Alzheimer’s disease (AD) or Parkinson’s disease (PD) is type 2 diabetes mellitus (T2DM). In several patient database analyses, T2DM has been identified as a risk factor for PD, indicating that insulin desensitization in the periphery may be a factor in initiating or accelerating the development of neurodegenerative processes 1,2. In AD, several epidemiological studies found a correlation between T2DM and an increased risk of developing AD at a later stage in life 3–8. In one investigation, T2DM had been identified as a risk factor that doubled the chance of developing AD 9. In a longitudinal cohort study that followed up the health status of people over time, glucose intolerance in a oral glucose tolerance test correlated to an increased risk of developing AD in people with significantly elevated blood glucose levels 10. Other studies arrived at similar conclusions 11. In PD, T2DM has also been identified as a risk factor 12–15. In the basal ganglia, dopaminergic transmission failure, insulin desensitization and energy depletion had been associated with T2DM 16.

Back to Top | Article Outline

Insulin signalling desensitizes in the brain

A key mechanism that appears to link T2DM with neurodegenerative disorders is the loss of insulin signalling in the brain. A biochemical analysis of brain tissue of AD patients showed a clear profile of insulin desensitization, even in people who were not diabetic 17–20. Insulin receptor subunits and insulin receptor substrate 1 were found to be hyperphosphorylated, a biochemical profile also seen in diabetic patients in the peripheral tissue 19,20. In PD, insulin desensitization was also observed in the key brain area such as the basal ganglia and substantia nigra 1,21,22. Energy utilization, mitochondrial function, insulin signalling and dopamine transmission were found to be compromised 21,23,24. It is interesting to note that these effects were also found in nondiabetic individuals. This demonstrates that insulin desensitization is not always dependent on glucose levels. However, patient data showed that a higher percentage of PD patients were diabetic or glucose intolerant compared with age-matched controls 2.

Back to Top | Article Outline

Insulin is a key growth factor

Insulin is an important growth factor that is essential for the homeostasis and cell growth and repair in neurons. Counterintuitively, glucose uptake in neurons is not insulin dependent, with the exception of large neurons that express the GLUT4 subtype 25,26. Hence, the brain had been commonly known as an ‘insulin insensitive’ organ 27. However, insulin and IGF-1 are important growth factors that activate cell growth, cell repair, gene expression, energy utilization and protein synthesis 28–31. This may explain why insulin desensitization in the brain increases the risk of developing neurodegenerative disorders such as AD and PD.

Back to Top | Article Outline

Treating Alzheimer’s disease patients with insulin

Just as insulin improves T2DM, treating AD patients with insulin shows improvements in cognition, attention, reducing levels of biomarkers for AD and normalizing brain energy utilization 32–35. Insulin cannot be given to people who are not diabetic. Administration of insulin by means of nasal application wherein it enters the brain more directly can circumvent the problem of inducing hypoglycaemia. Nasal application of insulin improved attention and memory formation even in nondiabetic people 34,36,37. A phase II clinical trial in AD patients showed improved cognition in patients with mild cognitive impairments (MCIs). It further improved the amyloid 1-40/1-42 ratio in the cerebrospinal fluid and increased brain activation as seen in 18F-fluorodeoxyglucose (18F-FDG)-PET scans, which measure brain activity and energy utilization, and showed improvement in mental tasks 38–40. However, similar to patients with T2DM, insulin delivery appears to enhance brain insulin desensitization and worsen cognitive decline 40. For a review, see Freiherr et al. 41 and Hölscher 42.

Back to Top | Article Outline

Type 2 diabetes mellitus drugs have neuroprotective properties

Drugs to treat T2DM and normalize insulin signalling are on the market. These are mimetics of the incretin hormone glucagon-like peptide 1 (GLP-1) 43,44. GLP-1 is a growth factor of the glucagon family type and has properties similar to that of insulin 31. These drugs do not affect blood glucose levels directly, and therefore are safe to be taken by people who are not diabetic 45. The drugs are well received and have a good safety record 46.

Several of these drugs can cross the blood–brain barrier, which demonstrates that there is a transporter for GLP-1, similar to other growth factors such as insulin or leptin 25,47–51.

There has been some discussion on whether glucagon-like peptide 1 receptors (GLP-1Rs) are expressed in neurons. A study that analysed RNA expression of the GLP-1R has demonstrated a wide distribution of GLP-1Rs in the brain, including the cortex, hippocampus and the substantia nigra – key brain areas in AD and PD disease development 52. Several antibody-based histological investigations of GLP-1R expression in the brain have been conducted since 53–59. However, one study has demonstrated that these antibodies may not be selective for the receptor followed 60, and a recent analysis of GLP-1R expression in the brain using a transgenic green fluorescent protein expression reporter mouse strain showed a significant expression of GLP-1Rs in the cortex, hippocampus area CA3, in the dentate gyrus and in others 61, putting the discussion to rest once and for all.

Back to Top | Article Outline

Glucagon-like peptide 1 mimetics show effects in animal models of Alzheimer’s disease

In several transgenic mouse models of AD, which express the human Swedish mutated form of the amyloid precursor protein and a mutated human form of presenilin-1, both mutations that lead to AD in humans, GLP-1 mimetics were neuroprotective. Liraglutide (Victoza) is in the market as a treatment for T2DM 62. Once-daily injections for 8 weeks reduced key parameters such as memory loss, synapse loss, reduced synaptic transmission, chronic inflammation in the brain and amyloid plaque load in the brain 63. The same treatment in aged transgenic mice with advanced amyloidosis still showed some protective effects, suggesting that treatment at later disease stages may still have benefits 64. When treated from an early age onward, the drug did prevent disease progression and has the potential to be used as a prophylactic 65. The GLP-1 mimetic lixisenatide (Lyxumia) also had similar neuroprotective effects as those of liraglutide 66. Liraglutide had clear protective effects in a mouse model of tau phosphorylation and tangle formation, a key biomarker for AD. In the human P301L-mutated tau-expressing mouse, a model of frontotemporal lobe dementia and amyotrophic lateral sclerosis, liraglutide reduced the amount of tangles and hyperphosphorylated tau 67. In the accelerated senescence SAMP8 mouse model, liraglutide also showed good protective effects on memory formation and neuronal loss 68. The GLP-1 mimetic exendin-4 (exenatide; Byetta and Bydureon) also showed good effects in a triple transgenic mouse model of AD 69.

Exendin-4 showed neuroprotective effects in other animal models of neurodegeneration as well 70–73. GLP-1 mimetics furthermore improve neuronal progenitor cell proliferation and neurogenesis in the mouse brain. In mouse models of AD and of diabetes, GLP-1 analogues can increase or normalize neuronal progenitor cell proliferation in the central nervous system 50,57,63,69,74–76. Testing analogues of the sister incretin glucose-dependent insulinotropic polypeptide (GIP) also showed significant effects in the amyloid precursor protein/presenilin-1 mouse model of AD 77–79.

Back to Top | Article Outline

Glucagon-like peptide 1 mimetics show effects in animal models of Parkinson’s disease

Exendin-4 has shown good neuroprotective effects in several mouse models of PD. In the 6-hydroxydopamine (6-OHDA) model of PD in which dopaminergic neurons are eliminated by 6-OHDA, the animals were treated for 3 weeks and showed functional recovery. In the substantia nigra, dopaminergic neurons were partly protected from the toxic effects of 6-OHDA 80.

This result was confirmed in a second study, which also used the 6-OHDA lesion technique and a second technique, the lipopolysaccharide-induced substantia nigra lesion. Exendin-4 reduced the lesions induced by the toxins. The levels of dopamine measured in the basal ganglia were also increased. The numbers of neurons in the substantia nigra were also higher than that in the lesion only group 81. In a third study, exendin-4 protected dopaminergic neurons and rescued motor function in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion mouse model of PD 59.

On comparing the more effective GLP-1 mimetics liraglutide and lixisenatide with exendin-4, it was found that both liraglutide and lixisenatide demonstrated good protective effects, whereas exendin-4 showed only minor protection in the MPTP mouse model of PD. Motor activity was partly rescued and dopaminergic neurons were protected in the substantia nigra. Expression of the dopamine biomarker tyrosine hydroxylase was also rescued in the liraglutide and lixisenatide treated mice. Proapoptotic cell signalling was reduced, whereas growth factor signalling was enhanced by both drugs 82. When testing the sister incretin GIP in the MPTP mouse model, it was found that the long-lasting protease-resistant analogue D-Ala2-GIP-glu-PAL showed good protective effects. Motor activity was partly rescued, and the number of dopaminergic neurons in the substantia nigra was increased. Synapse numbers were increased, and the cAMP/PKA/CREB growth factor second messenger pathway was shown to be activated by D-Ala2-GIP-glu-PAL 83.

New dual GLP-1 and GIP receptor agonists have been developed to treat T2DM. Some have already been tested in clinical trials and show superior performance compared with liraglutide 84. When testing a novel dual agonist in the MPTP mouse model of PD, it was found that it rescued motor activity, synapse numbers, and numbers of dopaminergic neurons in the substantia nigra and reduced chronic inflammation (Fig. 1). Interestingly, the expression of the neuroprotective growth factor brain-derived neurotropic factor was enhanced, which can explain some of the neuroprotective effects observed 85,86. Brain-derived neurotropic factor has clear protective effects on synaptic activity 87,88.

Fig. 1

Fig. 1

Back to Top | Article Outline

Clinical trials

The results obtained in the preclinical studies show an impressive range of neuroprotective effects of GLP-1 and GIP mimetics. As several GLP-1 mimetics are already on the market as treatments for T2DM with a better safety profile, clinical trials have started investigating the neuroprotective effects of exendin-4 or liraglutide in PD or AD patients.

Back to Top | Article Outline

Parkinson’s disease

A clinical pilot trial of exendin-4 in PD patients has been completed (clinical trials identifier: NCT01174810). This ‘proof of concept’ study tested the effects of exendin-4 in a randomized, open label trial in 45 patients. The drug was administered over 12 months, followed by a 2-month washout period. In a single-blinded rating of motor activity, clear improvements were found, and cognitive measures were improved in the drug group compared with controls. Exendin-4-treated patients had a mean improvement of 2.7 points at 12 months on the Movement Disorder Society unified Parkinson's disease rating, compared with a mean decline of 2.2 points in controls (P=0.037). Importantly, the drug group showed a clear improvement in the Mattis dementia rating scale 2 cognitive score, suggesting that exendin-4 has beneficial effects on cognition and memory 89. The group was retested 12 months after the trial was completed, and the clear differences between groups in motor performance and cognitive scores had not changed 90. This suggests that the difference between groups is not due to a placebo effect, as 12 months is too long a period for such subjective effects to last.

A phase II trial testing the once-weekly formulation of exendin-4 (Bydureon) has been completed (NCT01971242). The results will be reported shortly and initial observations suggest a good outcome.

A phase II trial testing liraglutide in PD patients is under preparation and will start in July 2016, testing 100 patients in a double-blind, placebo-controlled design.

Back to Top | Article Outline

Alzheimer’s disease

A randomized, double-blind clinical trial to assess the safety and efficacy of exendin-4 treatment in 230 MCI patients (early phase AD) is ongoing at the National Institutes of health/National Institute of Aging in the USA. This trial is being carried out to test the effects of exendin-4 on key parameters such as performance in the Clinical Dementia Rating scale sum-of-boxes, the Alzheimer’s Disease Assessment Scale cognitive subscale, behavioural and cognitive performance measures, changes in structural and functional MRI brain imaging, and hormonal and metabolic changes in cerebrospinal fluid and plasma AD biomarkers ( identifier: NCT01255163).

A small-scale trial with 34 patients has been completed in Denmark at the University of Aarhus. This double-blind, randomized trial investigated the effects of liraglutide versus placebo on MCI patients, using 18F-FDG-PET imaging to estimate cortical activity and Pittsburgh Compound-B (PIB) PIB-PET imaging to measure plaque load 91. Excitingly, there was a clear effect on brain 18F-FDG-PET activity. 18F-FDG is a modified glucose molecule, and the uptake correlates well with brain activity, synaptic activity and disease progression 92. Although the placebo group showed the expected reduction (≤20%) in the 18F-FDG-PET signal, the drug group showed no reduction at all and even demonstrated improved signalling in some brain areas (NCT01469351) 93.

A second larger scale phase II clinical trial with liraglutide in 206 MCI patients is ongoing in the UK. The trial has a randomized, placebo-controlled, double-blind design and will analyse 18F-FDG-PET brain activity, PET inflammation markers (microglia activation), MRI brain scan changes, cerebrospinal fluid samples for inflammation markers and amyloid/tau levels and cognitive tests such as the Alzheimer’s Disease Assessment Scale Exec score. Patient recruitment is currently ongoing (NCT01843075).

Back to Top | Article Outline


Conflicts of interest

The author is a named inventor on several patents that cover the use of GLP-1 or GIP analogues to treat Alzheimer's or Parkinson's disease. The patents are owned by Ulster and Lancaster Universities.

Back to Top | Article Outline


1. Moroo I, Yamada T, Makino H, Tooyama I, McGeer PL, McGeer EG, Hirayama K. Loss of insulin receptor immunoreactivity from the substantia nigra pars compacta neurons in Parkinson’s disease. Acta Neuropathol 1994; 87:343–348.
2. Aviles-Olmos I, Limousin P, Lees A, Foltynie T. Parkinson’s disease, insulin resistance and novel agents of neuroprotection. Brain 2013; 136 (Pt 2):374–384.
3. Strachan MW. Insulin and cognitive function in humans: experimental data and therapeutic considerations. Biochem Soc Trans 2005; 33 (Pt 5):1037–1040.
4. Haan MN. Therapy insight: type 2 diabetes mellitus and the risk of late-onset Alzheimer’s disease. Nat Clin Pract Neurol 2006; 2:159–166.
5. Luchsinger JA, Tang MX, Shea S, Mayeux R. Hyperinsulinemia and risk of Alzheimer disease. Neurology 2004; 63:1187–1192.
6. Ristow M. Neurodegenerative disorders associated with diabetes mellitus. J Mol Med (Berl) 2004; 82:510–529.
7. Biessels GJ, De Leeuw FE, Lindeboom J, Barkhof F, Scheltens P. Increased cortical atrophy in patients with Alzheimer’s disease and type 2 diabetes mellitus. J Neurol Neurosurg Psychiatry 2006; 77:304–307.
8. Leibson CL, Rocca WA, Hanson VA, Cha R, Kokmen E, O’Brien PC, Palumbo PJ. Risk of dementia among persons with diabetes mellitus: a population-based cohort study. Am J Epidemiol 1997; 145:301–308.
9. Janson J, Laedtke T, Parisi JE, O’Brien P, Petersen RC, Butler PC. Increased risk of type 2 diabetes in Alzheimer disease. Diabetes 2004; 53:474–481.
10. Ohara T, Doi Y, Ninomiya T, Hirakawa Y, Hata J, Iwaki T, et al.. Glucose tolerance status and risk of dementia in the community: the Hisayama study. Neurology 2011; 77:1126–1134.
11. Schrijvers EM, Witteman JC, Sijbrands EJ, Hofman A, Koudstaal PJ, Breteler MM. Insulin metabolism and the risk of Alzheimer disease: the Rotterdam study. Neurology 2010; 75:1982–1987.
12. Hu G, Jousilahti P, Bidel S, Antikainen R, Tuomilehto J. Type 2 diabetes and the risk of Parkinson’s disease. Diabetes Care 2007; 30:842–847.
13. Cereda E, Barichella M, Cassani E, Caccialanza R, Pezzoli G. Clinical features of Parkinson disease when onset of diabetes came first: a case–control study. Neurology 2012; 78:1507–1511.
14. Cereda E, Barichella M, Pedrolli C, Klersy C, Cassani E, Caccialanza R, Pezzoli G. Diabetes and risk of Parkinson’s disease: a systematic review and meta-analysis. Diabetes Care 2011; 34:2614–2623.
15. Lu L, Fu DL, Li HQ, Liu AJ, Li JH, Zheng GQ. Diabetes and risk of Parkinson’s disease: an updated meta-analysis of case–control studies. PLoS One 2014; 9:e85781.
16. Lima MM, Targa AD, Noseda AC, Rodrigues LS, Delattre AM, dos Santos FV, et al.. Does Parkinson’s disease and type-2 diabetes mellitus present common pathophysiological mechanisms and treatments? CNS Neurol Disord Drug Targets 2014; 13:418–428.
17. Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, et al.. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease – is this type 3 diabetes? J Alzheimers Dis 2005; 7:63–80.
18. Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, de la Monte SM. Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer’s disease. J Alzheimers Dis 2006; 9:13–33.
19. 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. J Clin Invest 2012; 122:1316–1338.
20. Moloney AM, Griffin RJ, Timmons S, O’Connor R, Ravid R, O’Neill C. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol Aging 2010; 31:224–243.
21. Morris JK, Zhang H, Gupte AA, Bomhoff GL, Stanford JA, Geiger PC. Measures of striatal insulin resistance in a 6-hydroxydopamine model of Parkinson’s disease. Brain Res 2008; 1240:185–195.
22. Pellecchia MT, Santangelo G, Picillo M, Pivonello R, Longo K, Pivonello C, et al.. Insulin-like growth factor-1 predicts cognitive functions at 2-year follow-up in early, drug-naïve Parkinson’s disease. Eur J Neurol 2014; 21:802–807.
23. Morris JK, Bomhoff GL, Gorres BK, Davis VA, Kim J, Lee PP, et al.. Insulin resistance impairs nigrostriatal dopamine function. Exp Neurol 2011; 231:171–180.
24. Numao A, Suzuki K, Miyamoto M, Miyamoto T, Hirata K. Clinical correlates of serum insulin-like growth factor-1 in patients with Parkinson’s disease, multiple system atrophy and progressive supranuclear palsy. Parkinsonism Relat Disord 2014; 20:212–216.
25. Banks WA. The source of cerebral insulin. Eur J Pharmacol 2004; 490:5–12.
26. Fernando RN, Albiston AL, Chai SY. The insulin-regulated aminopeptidase IRAP is colocalised with GLUT4 in the mouse hippocampus – potential role in modulation of glucose uptake in neurones? Eur J Neurosci 2008; 28:588–598.
27. Ghasemi R, Haeri A, Dargahi L, Mohamed Z, Ahmadiani A. Insulin in the brain: sources, localization and functions. Mol Neurobiol 2013; 47:145–171.
28. Carro E, Torres-Aleman I. The role of insulin and insulin-like growth factor I in the molecular and cellular mechanisms underlying the pathology of Alzheimer’s disease. Eur J Pharmacol 2004; 490:127–133.
29. Craft S, Cholerton B, Baker LD. Insulin and Alzheimer’s disease: untangling the web. J Alzheimers Dis 2013; 33 (Suppl 1):S263–S275.
30. Hoyer S. Glucose metabolism and insulin receptor signal transduction in Alzheimer disease. Eur J Pharmacol 2004; 490:115–125.
31. Hölscher C. Insulin, incretins and other growth factors as potential novel treatments for Alzheimer’s and Parkinson’s diseases. Biochem Soc Trans 2014; 42:593–599.
32. Watson GS, Craft S. Modulation of memory by insulin and glucose: neuropsychological observations in Alzheimer’s disease. Eur J Pharmacol 2004; 490:97–113.
33. Zhao WQ, Chen H, Quon MJ, Alkon DL. Insulin and the insulin receptor in experimental models of learning and memory. Eur J Pharmacol 2004; 490:71–81.
34. Reger MA, Watson GS, Green PS, Baker LD, Cholerton B, Fishel MA, et al.. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis 2008; 13:323–331.
35. Okereke OI, Selkoe DJ, Pollak MN, Stampfer MJ, Hu FB, Hankinson SE, Grodstein F. A profile of impaired insulin degradation in relation to late-life cognitive decline: a preliminary investigation. Int J Geriatr Psychiatry 2009; 24:177–182.
36. Reger MA, Watson GS, Green PS, Wilkinson CW, Baker LD, Cholerton B, et al.. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology 2008; 70:440–448.
37. Craft S. Insulin resistance and Alzheimer’s disease pathogenesis: potential mechanisms and implications for treatment. Curr Alzheimer Res 2007; 4:147–152.
38. Craft S. A randomized, placebo-controlled trial of intranasal insulin in amnestic MCI and early Alzheimer’s. Hawaii, USA: ICAD conference; 10–15 July 2010. Abstract P3–P455.
39. Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, et al.. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol 2012; 69:29–38.
40. Claxton A, Baker LD, Hanson A, Trittschuh EH, Cholerton B, Morgan A, et al.. Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer’s disease dementia. J Alzheimers Dis 2015; 44:897–906.
41. Freiherr J, Hallschmid M, Frey WH II, Brünner YF, Chapman CD, Hölscher C, et al.. Intranasal insulin as a treatment for Alzheimer’s disease: a review of basic research and clinical evidence. CNS Drugs 2013; 27:505–514.
42. Hölscher C. First clinical data of the neuroprotective effects of nasal insulin application in patients with Alzheimer’s disease. Alzheimers Dement 2014; 10 (Suppl):S33–S37.
43. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007; 132:2131–2157.
44. Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab 2013; 17:819–837.
45. Lean ME, Carraro R, Finer N, Hartvig H, Lindegaard ML, Rössner S, et al.. NN8022-1807 Investigators. Tolerability of nausea and vomiting and associations with weight loss in a randomized trial of liraglutide in obese, non-diabetic adults. Int J Obes (Lond) 2014; 38:689–697.
46. Baggio LL, Kim JG, Drucker DJ. Chronic exposure to GLP-1R agonists promotes homologous GLP-1 receptor desensitization in vitro but does not attenuate GLP-1R-dependent glucose homeostasis in vivo. Diabetes 2004; 53 (Suppl 3):S205–S214.
47. Banks WA, Jaspan JB, Kastin AJ. Selective, physiological transport of insulin across the blood–brain barrier: novel demonstration by species-specific radioimmunoassays. Peptides 1997; 18:1257–1262.
48. Kastin AJ, Akerstrom V, Pan W. Interactions of glucagon-like peptide-1 (GLP-1) with the blood–brain barrier. J Mol Neurosci 2002; 18:7–14.
49. Kastin AJ, Akerstrom V. Entry of exendin-4 into brain is rapid but may be limited at high doses. Int J Obes Relat Metab Disord 2003; 27:313–318.
50. Hunter K, Hölscher C. Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci 2012; 13:33.
51. Secher A, Jelsing J, Baquero AF, Hecksher-Sørensen J, Cowley MA, Dalbøge LS, et al.. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J Clin Invest 2014; 124:4473–4488.
52. 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. J Comp Neurol 1999; 403:261–280.
53. Teramoto S, Miyamoto N, Yatomi K, Tanaka Y, Oishi H, Arai H, et al.. Exendin-4, a glucagon-like peptide-1 receptor agonist, provides neuroprotection in mice transient focal cerebral ischemia. J Cereb Blood Flow Metab 2011; 31:1696–1705.
54. Darsalia V, Ortsäter H, Olverling A, Darlöf E, Wolbert P, Nyström T, et al.. The DPP-4 inhibitor linagliptin counteracts stroke in the normal and diabetic mouse brain: a comparison with glimepiride. Diabetes 2013; 62:1289–1296.
55. Darsalia V, Mansouri S, Ortsäter H, Olverling A, Nozadze N, Kappe C, et al.. Glucagon-like peptide-1 receptor activation reduces ischaemic brain damage following stroke in Type 2 diabetic rats. Clin Sci (Lond) 2012; 122:473–483.
56. Lee CH, Yan B, Yoo KY, Choi JH, Kwon SH, Her S, et al.. Ischemia-induced changes in glucagon-like peptide-1 receptor and neuroprotective effect of its agonist, exendin-4, in experimental transient cerebral ischemia. J Neurosci Res 2011; 89:1103–1113.
57. 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. Nat Med 2003; 9:1173–1179.
58. Hamilton A, Holscher C. Receptors for the insulin-like peptide GLP-1 are expressed on neurons in the CNS. Neuroreport 2009; 20:1161–1166.
59. Li Y, Perry T, Kindy MS, Harvey BK, Tweedie D, Holloway HW, et al.. GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism. Proc Natl Acad Sci USA 2009; 106:1285–1290.
60. Drucker DJ. Incretin action in the pancreas: potential promise, possible perils, and pathological pitfalls. Diabetes 2013; 62:3316–3323.
61. Cork SC, Richards JE, Holt MK, Gribble FM, Reimann F, Trapp S. Distribution and characterisation of glucagon-like peptide-1 receptor expressing cells in the mouse brain. Mol Metab 2015; 4:718–731.
62. Courrèges JP, Vilsbøll T, Zdravkovic M, Le-Thi T, Krarup T, Schmitz O, et al.. Beneficial effects of once-daily liraglutide, a human glucagon-like peptide-1 analogue, on cardiovascular risk biomarkers in patients with Type 2 diabetes. Diabet Med 2008; 25:1129–1131.
63. McClean PL, Parthsarathy V, Faivre E, Hölscher C. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease. J Neurosci 2011; 31:6587–6594.
64. McClean PL, Hölscher 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.
65. McClean PL, Jalewa J, Hölscher C. Prophylactic liraglutide treatment prevents amyloid plaque deposition, chronic inflammation and memory impairment in APP/PS1 mice. Behav Brain Res 2015; 293:96–106.
66. McClean PL, Hölscher C. Lixisenatide, a drug developed to treat type 2 diabetes, shows neuroprotective effects in a mouse model of Alzheimer’s disease. Neuropharmacology 2014; 86:241–258.
67. Hansen HH, Barkholt P, Fabricius K, Jelsing J, Terwel D, Pyke C, et al.. The GLP-1 receptor agonist liraglutide reduces pathology-specific tau phosphorylation and improves motor function in a transgenic hTauP301L mouse model of tauopathy. Brain Res 2016; 1634:158–170.
68. Hansen HH, Fabricius K, Barkholt P, Niehoff ML, Morley JE, Jelsing J, et al.. The GLP-1 receptor agonist liraglutide improves memory function and increases hippocampal CA1 neuronal numbers in a senescence-accelerated mouse model of alzheimer’s disease. J Alzheimers Dis 2015; 46:877–888.
69. 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. J Alzheimers Dis 2010; 19:1205–1219.
70. Perry T, Greig NH. Enhancing central nervous system endogenous GLP-1 receptor pathways for intervention in Alzheimer’s disease. Curr Alzheimer Res 2005; 2:377–385.
71. Rachmany L, Tweedie D, Li Y, Rubovitch V, Holloway HW, Miller J, et al.. Exendin-4 induced glucagon-like peptide-1 receptor activation reverses behavioral impairments of mild traumatic brain injury in mice. Age (Dordr) 2013; 35:1621–1636.
72. Eakin K, Li Y, Chiang YH, Hoffer BJ, Rosenheim H, Greig NH, Miller JP. Exendin-4 ameliorates traumatic brain injury-induced cognitive impairment in rats. PLoS One 2013; 8:e82016.
73. Perry T, Holloway HW, Weerasuriya A, Mouton PR, Duffy K, Mattison JA, Greig NH. Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy. Exp Neurol 2007; 203:293–301.
74. Porter DW, Irwin N, Flatt PR, Hölscher C, Gault VA. Prolonged GIP receptor activation improves cognitive function, hippocampal synaptic plasticity and glucose homeostasis in high-fat fed mice. Eur J Pharmacol 2011; 650:688–693.
75. Porter DW, Kerr BD, Flatt PR, Holscher C, Gault VA. Four weeks administration of Liraglutide improves memory and learning as well as glycaemic control in mice with high fat dietary-induced obesity and insulin resistance. Diabetes Obes Metab 2010; 12:891–899.
76. Hamilton A, Patterson S, Porter D, Gault VA, Holscher C. Novel GLP-1 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain. J Neurosci Res 2011; 89:481–489.
77. Faivre E, Hölscher C. D-Ala2GIP facilitated synaptic plasticity and reduces plaque load in aged wild type mice and in an Alzheimer’s disease mouse model. J Alzheimers Dis 2013; 35:267–283.
78. Faivre E, Hölscher C. Neuroprotective effects of D-Ala(2)GIP on Alzheimer’s disease biomarkers in an APP/PS1 mouse model. Alzheimers Res Ther 2013; 5:20.
79. Duffy AM, Hölscher C. The incretin analogue D-Ala2GIP reduces plaque load, astrogliosis and oxidative stress in an APP/PS1 mouse model of Alzheimer’s disease. Neuroscience 2013; 228:294–300.
80. Bertilsson G, Patrone C, Zachrisson O, Andersson A, Dannaeus K, Heidrich J, et al.. Peptide hormone exendin-4 stimulates subventricular zone neurogenesis in the adult rodent brain and induces recovery in an animal model of Parkinson’s disease. J Neurosci Res 2008; 86:326–338.
81. Harkavyi A, Abuirmeileh A, Lever R, Kingsbury AE, Biggs CS, Whitton PS. Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson’s disease. J Neuroinflammation 2008; 5:19.
82. Liu W, Jalewa J, Sharma M, Li G, Li L, Hölscher C. Neuroprotective effects of lixisenatide and liraglutide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Neuroscience 2015; 303:42–50.
83. Li Y, Liu W, Li L, Hölscher C. Neuroprotective effects of a GIP analogue in the MPTP Parkinson’s disease mouse model. Neuropharmacology 2016; 101:255–263.
84. Finan B, Ma T, Ottaway N, et al.. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci Transl Med 2013; 5:209ra151.
85. Cao L, Li D, Feng P, Li L, Xue GF, Li G, Hölscher C. A novel dual GLP-1 and GIP incretin receptor agonist is neuroprotective in a mouse model of Parkinson’s disease by reducing chronic inflammation in the brain. Neuroreport 2016; 27:384–391.
86. Ji C, Xue GF, Lijun C, Feng P, Li D, Li L, et al.. A novel dual GLP-1 and GIP receptor agonist is neuroprotective in the MPTP mouse model of Parkinson’s disease by increasing expression of BDNF. Brain Res 2016; 1634:1–11.
87. Blurton-Jones M, Kitazawa M, Martinez-Coria H, Castello NA, Müller FJ, Loring JF, et al.. Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proc Natl Acad Sci USA 2009; 106:13594–13599.
88. Allen SJ, Watson JJ, Shoemark DK, Barua NU, Patel NK. GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol Ther 2013; 138:155–175.
89. Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Ell P, Soderlund T, et al.. Exenatide and the treatment of patients with Parkinson’s disease. J Clin Invest 2013; 123:2730–2736.
90. Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Kahan J, Ell P, et al.. Motor and cognitive advantages persist 12 months after exenatide exposure in Parkinson’s disease. J Parkinsons Dis 2014; 4:337–344.
91. Egefjord L, Gejl M, Møller A, Brændgaard H, Gottrup H, Antropova O, et al.. Effects of liraglutide on neurodegeneration, blood flow and cognition in Alzheimer’s disease – protocol for a controlled, randomized double-blinded trial. Dan Med J 2012; 59:A4519.
92. Femminella GD, Edison P. Evaluation of neuroprotective effect of glucagon-like peptide 1 analogs using neuroimaging. Alzheimers Dement 2014; 10 (Suppl):S55–S61.
93. Gejl M, Gjedde A, Egefjord L, Møller A, Hansen SB, Vang K, et al.. In Alzheimer’s disease, six-month treatment with GLP-1 analogue prevents decline of brain glucose metabolism: randomized, placebo-controlled, double-blind clinical trial. Front Aging Neurosci 2016; 8:108.

growth factors; incretins; insulin; neurodegeneration

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.