Skip to main content

Advertisement

SpringerLink
Log in

A review of glucoregulatory hormones potentially applicable to the treatment of Alzheimer’s disease: mechanism and brain delivery

  • Review
  • Published:
Journal of Pharmaceutical Investigation Aims and scope Submit manuscript

Abstract

Background

Despite the accumulating research efforts, the current treatment of Alzheimer’s disease (AD) remains far from achieving any clinical success in modifying the underlying pathological conditions.

Area covered

Therefore, it is an imminent task to discover more potent anti-AD drugs, as well as deepen the understanding of the disease mechanism. A group of potential drug candidates for the AD may be the hormones that involve in the glucose homeostasis and lipid metabolism, as the type 2 diabetes mellitus (T2DM) and obesity have been recognized as major risk factors of the AD.

Expert opinion

Indeed, up to date, many researches have reported the potential therapeutic effects of the glucoregulatory hormones, such as GLP-1, adipokines (adiponectin, leptin), and ghrelin. However, despite their anti-AD activity, there remains a bottleneck challenge for their successful delivery to the brain. In the present review, we provide an overview of the therapeutic potentials of glucoregulatory hormones and their receptor agonists for the AD. In the latter part, we also discuss the delivery strategies across the blood brain barrier, with a particular focus on previous studies that used the Trojan horse technology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Abbas T, Faivre E, Hölscher C (2009) Impairment of synaptic plasticity and memory formation in GLP-1 receptor KO mice: Interaction between type 2 diabetes and Alzheimer’s disease. Behav Brain Res 205:265–271

    Article  CAS  PubMed  Google Scholar 

  • Ahn Y-J, Shin H-J, Jeong E, An H-S, Lee J-Y, Jang H-M, Kim K-E, Lee J, Shin M-C, Roh G-S (2021) Exendin-4 pretreatment attenuates kainic acid-induced hippocampal neuronal death. Cells 10:2527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ali T, Yoon GH, Shah SA, Lee HY, Kim MO (2015) Osmotin attenuates amyloid beta-induced memory impairment, tau phosphorylation and neurodegeneration in the mouse hippocampus. Sci Rep 5:11708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ali T, Rehman SU, Khan A, Badshah H, Abid NB, Kim MW, Jo MH, Chung SS, Lee HG, Rutten BPF, Kim MO (2021) Adiponectin-mimetic novel nonapeptide rescues aberrant neuronal metabolic-associated memory deficits in Alzheimer’s disease. Mol Neurodegener 16:23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Amatya R, Park T, Hwang S, Yang J, Lee Y, Cheong H, Moon C, Kwak HD, Min KA, Shin MC (2020) Drug delivery strategies for enhancing the therapeutic efficacy of toxin-derived anti-diabetic peptides. Toxins 12:313

    Article  CAS  PubMed Central  Google Scholar 

  • Anderson BM, Jacobson L, Novakovic ZM, Grasso P (2017) Oral delivery of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3, synthetic peptide leptin mimetics: immunofluorescent localization in the mouse hypothalamus. Brain Res 1664:1–8

    Article  CAS  PubMed  Google Scholar 

  • Anderson BM, Hirschstein Z, Novakovic ZM, Grasso P (2020) MA-[d-Leu-4]-OB3, a small molecule synthetic peptide leptin mimetic, mirrors the cognitive enhancing action of leptin in a mouse model of type 1 diabetes mellitus and Alzheimer’s disease-like cognitive impairment. Int J Pept Res Ther 26:1243–1249

    Article  CAS  Google Scholar 

  • Ariyasu H, Takaya K, Tagami T, Ogawa Y, Hosoda K, Akamizu T, Suda M, Koh T, Natsui K, Toyooka S, Shirakami G, Usui T, Shimatsu A, Doi K, Hosoda H, Kojima M, Kangawa K, Nakao K (2001) Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J Clin Endocrinol Metab 86:4753–4758

    Article  CAS  PubMed  Google Scholar 

  • Arora S, Layek B, Singh J (2020a) Design and validation of liposomal ApoE2 gene delivery system to evade blood–brain barrier for effective treatment of Alzheimer’s disease. Mol Pharm 18:714–725

    Article  PubMed  Google Scholar 

  • Arora S, Sharma D, Singh J (2020b) GLUT-1: an effective target to deliver brain-derived neurotrophic factor gene across the blood brain barrier. ACS Chem Neurosci 11:1620–1633

    Article  CAS  PubMed  Google Scholar 

  • Ballabh P, Braun A, Nedergaard M (2004) The blood–brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis 16:1–13

    Article  CAS  PubMed  Google Scholar 

  • Banks WA (2012) Drug delivery to the brain in Alzheimer’s disease: consideration of the blood–brain barrier. Adv Drug Deliv Rev 64:629–639

    Article  CAS  PubMed  Google Scholar 

  • Batista AF, Forny-Germano L, Clarke JR, Silva LENM, Brito-Moreira J, Boehnke SE, Winterborn A, Coe BC, Lablans A, Vital JF (2018) The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non-human primate model of Alzheimer’s disease. J Pathol 245:85–100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Batista AF, Bodart-Santos V, De Felice FG, Ferreira ST (2019) Neuroprotective actions of glucagon-like peptide-1 (GLP-1) analogues in Alzheimer’s and Parkinson’s diseases. CNS Drugs 33:209–223

    Article  PubMed  Google Scholar 

  • Bendlin BB (2019) Antidiabetic therapies and Alzheimer disease. Dialogues Clin Neurosci 21:83–91

    Article  PubMed  PubMed Central  Google Scholar 

  • Bi G, Zhang Q, Zhang Y, Liang Y, Wang X, Li Y, Dong R, Liu Z, Qu H (2018) Therapeutic effect of transmembrane TAT-tCNTF via Erk and Akt activation using in vitro and in vivo models of Alzheimer’s disease. Int J Clin Exp Pathol 11:1855–1865

    PubMed  PubMed Central  Google Scholar 

  • Bien-Ly N, Yu YJ, Bumbaca D, Elstrott J, Boswell CA, Zhang Y, Luk W, Lu Y, Dennis MS, Weimer RM (2014) Transferrin receptor (TfR) trafficking determines brain uptake of TfR antibody affinity variants. J Exp Med 211:233–244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boado RJ, Zhang Y, Zhang Y, Pardridge WM (2007a) Humanization of anti-human insulin receptor antibody for drug targeting across the human blood–brain barrier. Biotechnol Bioeng 96:381–391

    Article  CAS  PubMed  Google Scholar 

  • Boado RJ, Zhang Y, Zhang Y, Xia C-F, Pardridge WM (2007b) Fusion antibody for Alzheimer’s disease with bidirectional transport across the blood−brain barrier and Aβ fibril disaggregation. Bioconjug Chem 18:447–455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boado RJ, Lu JZ, Hui EKW, Pardridge WM (2010a) IgG-single chain Fv fusion protein therapeutic for alzheimer’s disease: Expression in CHO cells and pharmacokinetics and brain delivery in the rhesus monkey. Biotechnol Bioeng 105:627–635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boado RJ, Zhou Q-H, Lu JZ, Hui EK-W, Pardridge WM (2010b) Pharmacokinetics and brain uptake of a genetically engineered bifunctional fusion antibody targeting the mouse transferrin receptor. Mol Pharm 7:237–244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boado RJ, Hui EK-W, Lu JZ, Sumbria RK, Pardridge WM (2013) Blood-brain barrier molecular trojan horse enables imaging of brain uptake of radioiodinated recombinant protein in the rhesus monkey. Bioconjug Chem 24:1741–1749

    Article  CAS  PubMed  Google Scholar 

  • Boado RJ, Lu JZ, Hui EK-W, Pardridge WM (2014) Insulin receptor antibody–sulfamidase fusion protein penetrates the primate blood–brain barrier and reduces glycosoaminoglycans in Sanfilippo type A cells. Mol Pharm 11:2928–2934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boado RJ, Lu JZ, Hui EK-W, Pardridge WM (2018) Reduction in brain heparan sulfate with systemic administration of an IgG Trojan horse–sulfamidase fusion protein in the mucopolysaccharidosis type IIIA mouse. Mol Pharm 15:602–608

    Article  CAS  PubMed  Google Scholar 

  • Bonfili L, Cuccioloni M, Cecarini V, Mozzicafreddo M, Palermo FA, Cocci P, Angeletti M, Eleuteri AM (2013) Ghrelin induces apoptosis in colon adenocarcinoma cells via proteasome inhibition and autophagy induction. Apoptosis 18:1188–1200

    Article  CAS  PubMed  Google Scholar 

  • Bourassa P, Alata W, Tremblay C, Paris-Robidas S, Calon F (2019) Transferrin receptor-mediated uptake at the blood–brain barrier is not impaired by Alzheimer’s disease neuropathology. Mol Pharm 16:583–594

    Article  CAS  PubMed  Google Scholar 

  • Breijyeh Z, Karaman R (2020) Comprehensive review on Alzheimer’s disease: causes and treatment. Molecules 25:5789

    Article  CAS  PubMed Central  Google Scholar 

  • Brubaker P, Drucker D (2002) Structure-function of the glucagon receptor family of G protein-coupled receptors: the glucagon, GIP, GLP-1, and GLP-2 receptors. Recept Channels 8:179–188

    Article  CAS  PubMed  Google Scholar 

  • Bu G, Maksymovitch EA, Nerbonne JM, Schwartz AL (1994) Expression and function of the low density lipoprotein receptor-related protein (LRP) in mammalian central neurons. J Biol Chem 269:18521–18528

    Article  CAS  PubMed  Google Scholar 

  • Calsolaro V, Edison P (2015) Novel GLP-1 (glucagon-like peptide-1) analogues and insulin in the treatment for Alzheimer’s disease and other neurodegenerative diseases. CNS Drugs 29:1023–1039

    Article  CAS  PubMed  Google Scholar 

  • Cao X, Zhu M, He Y, Chu W, Du Y, Du H (2018a) Increased serum acylated ghrelin levels in patients with mild cognitive impairment. J Alzheimers Dis 61:545–552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cao Y, Holscher C, Hu MM, Wang T, Zhao F, Bai Y, Zhang J, Wu MN, Qi JS (2018b) DA5-CH, a novel GLP-1/GIP dual agonist, effectively ameliorates the cognitive impairments and pathology in the APP/PS1 mouse model of Alzheimer’s disease. Eur J Pharmacol 827:215–226

    Article  CAS  PubMed  Google Scholar 

  • Chan K-H, Lam KS-L, Cheng O-Y, Kwan JS-C, Ho PW-L, Cheng KK-Y, Chung SK, Ho JW-M, Guo VY, Xu A (2012) Adiponectin is protective against oxidative stress induced cytotoxicity in amyloid-beta neurotoxicity. PLoS ONE 7:e52354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen Z-L, Huang M, Wang X-R, Fu J, Han M, Shen Y-Q, Xia Z, Gao J-Q (2016) Transferrin-modified liposome promotes α-mangostin to penetrate the blood–brain barrier. Nanomedicine 12:421–430

    Article  CAS  PubMed  Google Scholar 

  • Cheng Z, Zhang J, Liu H, Li Y, Zhao Y, Yang E (2010) Central nervous system penetration for small molecule therapeutic agents does not increase in multiple sclerosis-and Alzheimer’s disease-related animal models despite reported blood-brain barrier disruption. Drug Metab Dispos 38:1355–1361

    Article  CAS  PubMed  Google Scholar 

  • Chiorazzi A, Wozniak KM, Rais R, Wu Y, Gadiano AJ, Farah MH, Liu Y, Canta A, Alberti P, Rodriguez-Menendez V, Meregalli C, Fumagalli G, Monza L, Pozzi E, Vornov JJ, Polydefkis M, Pietra C, Slusher BS, Cavaletti G (2018) Ghrelin agonist HM01 attenuates chemotherapy-induced neurotoxicity in rodent models. Eur J Pharmacol 840:89–103

    Article  CAS  PubMed  Google Scholar 

  • Choe HJ, Cho YM (2021) Peptidyl and non-peptidyl oral glucagon-like peptide-1 receptor agonists. Endocrinol Metab 36:22–29

    Article  CAS  Google Scholar 

  • Choudhari M, Hejmady S, Saha RN, Damle S, Singhvi G, Alexander A, Kesharwani P, Dubey SK (2021) Evolving new-age strategies to transport therapeutics across the blood-brain-barrier. Int J Pharm 599:120351

    Article  CAS  PubMed  Google Scholar 

  • Chua L-M, Lim M-L, Chong P-R, Hu ZP, Cheung NS, Wong B-S (2012) Impaired neuronal insulin signaling precedes Aβ 42 Accumulation in female AβPPsw/PS1ΔE9 Mice. J Alzheimers Dis 29:783–791

    Article  CAS  PubMed  Google Scholar 

  • Couch JA, Yu YJ, Zhang Y, Tarrant JM, Fuji RN, Meilandt WJ, Solanoy H, Tong RK, Hoyte K, Luk W (2013) Addressing safety liabilities of TfR bispecific antibodies that cross the blood-brain barrier. Sci Transl Med 5:183ra157

    Article  Google Scholar 

  • Crombez D, Delcambre S, Nonclercq D, Vander Elst L, Laurent S, Cnop M, Muller RN, Burtea C (2020) Modulation of adiponectin receptors AdipoR1 and AdipoR2 by phage display-derived peptides in in vitro and in vivo models. J Drug Target 28:831–851

    Article  CAS  PubMed  Google Scholar 

  • Cummings J, Lee G, Ritter A, Sabbagh M, Zhong K (2020) Alzheimer’s disease drug development pipeline: 2020. Alzheimers Dement 6:e12050

    Google Scholar 

  • Cummings J, Aisen P, Lemere C, Atri A, Sabbagh M, Salloway S (2021) Aducanumab produced a clinically meaningful benefit in association with amyloid lowering. Alzheimers Res Ther 13:98

    Article  PubMed  PubMed Central  Google Scholar 

  • Demeule M, Beaudet N, Régina A, Besserer-Offroy Ë, Murza A, Tétreault P, Belleville K, Ché C, Larocque A, Thiot C (2014) Conjugation of a brain-penetrant peptide with neurotensin provides antinociceptive properties. J Clin Invest 124:1199–1213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dennis MS, Watts RJ (2012) Transferrin antibodies into the brain. Neuropsychopharmacology 37:302–303

    Article  PubMed  Google Scholar 

  • Denver RJ, Bonett RM, Boorse GC (2011) Evolution of leptin structure and function. Neuroendocrinology 94:21–38

    Article  CAS  PubMed  Google Scholar 

  • Diano S, Farr SA, Benoit SC, Mcnay EC, Da Silva I, Horvath B, Gaskin FS, Nonaka N, Jaeger LB, Banks WA, Morley JE, Pinto S, Sherwin RS, Xu L, Yamada KA, Sleeman MW, Tschop MH, Horvath TL (2006) Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci 9:381–388

    Article  CAS  PubMed  Google Scholar 

  • Doherty GH, Beccano-Kelly D, Yan SD, Gunn-Moore FJ, Harvey J (2013) Leptin prevents hippocampal synaptic disruption and neuronal cell death induced by amyloid beta. Neurobiol Aging 34:226–237

    Article  CAS  PubMed  Google Scholar 

  • Dos Santos RB, Kanekiyo T, Singh J (2019) ApoE-2 brain-targeted gene therapy through transferrin and penetratin tagged liposomal nanoparticles. Pharm Res 36:161

    Article  Google Scholar 

  • Duro-Castano A, Borrás C, Herranz-Pérez V, Blanco-Gandía MC, Conejos-Sánchez I, Armiñán A, Mas-Bargues C, Inglés M, Miñarro J, Rodríguez-Arias M (2021) Targeting Alzheimer’s disease with multimodal polypeptide-based nanoconjugates. Sci Adv 7:eabf9180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duwa R, Jeong J-H, Yook S (2021) Development of immunotherapy and nanoparticles-based strategies for the treatment of Parkinson’s disease. J Pharm Investig 51:465–481

    Article  CAS  Google Scholar 

  • Emami J, Rezazadeh M, Sadeghi H, Khadivar K (2017) Development and optimization of transferrin-conjugated nanostructured lipid carriers for brain delivery of paclitaxel using Box-Behnken design. Pharm Dev Technol 22:370–382

    Article  CAS  PubMed  Google Scholar 

  • Eng J, Kleinman WA, Singh L, Singh G, Raufman J-P (1992) Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem 267:7402–7405

    Article  CAS  PubMed  Google Scholar 

  • Erickson MA, Banks WA (2013) Blood–brain barrier dysfunction as a cause and consequence of Alzheimer’s disease. J Cereb Blood Flow Metab 33:1500–1513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Erşahin M, Øzsavcı D, Şener A, Øzakpınar ØB, Toklu HZ, Akakin D, Şener G, Yeğen BÉ (2013) Obestatin alleviates subarachnoid haemorrhage-induced oxidative injury in rats via its anti-apoptotic and antioxidant effects. Brain Inj 27:1181–1189

    Article  PubMed  Google Scholar 

  • Eslami M, Sadeghi B, Goshadrou F (2018) Chronic ghrelin administration restores hippocampal long-term potentiation and ameliorates memory impairment in rat model of Alzheimer’s disease. Hippocampus 28:724–734

    Article  CAS  PubMed  Google Scholar 

  • Forny-Germano L, De Felice FG, Vieira MNDN (2019) The role of leptin and adiponectin in obesity-associated cognitive decline and Alzheimer’s disease. Front Neurosci 12:1027

    Article  PubMed  PubMed Central  Google Scholar 

  • Friden PM, Walus LR, Musso GF, Taylor MA, Malfroy B, Starzyk RM (1991) Anti-transferrin receptor antibody and antibody-drug conjugates cross the blood-brain barrier. Proc Natl Acad Sci U S A 88:4771–4775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Friden PM, Walus LR, Watson P, Kozarich J, Backman C, Bergman H, Hoffer B, Bloom F, Granholm A (1993) Blood-brain barrier penetration and in vivo activity of an NGF conjugate. Science 259:373–377

    Article  CAS  PubMed  Google Scholar 

  • Gaillard PJ, Visser CC, De Boer AG (2005) Targeted delivery across the blood–brain barrier. Expert Opin Drug Deliv 2:299–309

    Article  CAS  PubMed  Google Scholar 

  • Garabadu D, Verma J (2019) Exendin-4 attenuates brain mitochondrial toxicity through PI3K/Akt-dependent pathway in amyloid beta (1–42)-induced cognitive deficit rats. Neurochem Int 128:39–49

    Article  CAS  PubMed  Google Scholar 

  • Gargantini E, Lazzari L, Settanni F, Taliano M, Trovato L, Gesmundo I, Ghigo E, Granata R (2016) Obestatin promotes proliferation and survival of adult hippocampal progenitors and reduces amyloid-β-induced toxicity. Mol Cell Endocrinol 422:18–30

    Article  CAS  PubMed  Google Scholar 

  • Gengler S, Mcclean PL, Mccurtin R, Gault VA, Hölscher C (2012) Val (8) GLP-1 rescues synaptic plasticity and reduces dense core plaques in APP/PS1 mice. Neurobiol Aging 33:265–276

    Article  CAS  PubMed  Google Scholar 

  • Graebner AK, Iyer M, Carter ME (2015) Understanding how discrete populations of hypothalamic neurons orchestrate complicated behavioral states. Front Syst Neurosci 9:111

    Article  PubMed  PubMed Central  Google Scholar 

  • Grasso P, Rozhavskaya-Arena M, Leinung MC, Lee DW (2001) [D-LEU-4]-OB3, a synthetic leptin agonist, improves hyperglycemic control in C57BL/6J ob/ob mice. Regul Pept 101:123–129

    Article  CAS  PubMed  Google Scholar 

  • Greco SJ, Sarkar S, Johnston JM, Zhu X, Su B, Casadesus G, Ashford JW, Smith MA, Tezapsidis N (2008) Leptin reduces Alzheimer’s disease-related tau phosphorylation in neuronal cells. Biochem Biophys Res Commun 376:536–541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guan XM, Yu H, Palyha OC, Mckee KK, Feighner SD, Sirinathsinghji DJ, Smith RG, Van Der Ploeg LH, Howard AD (1997) Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res Mol Brain Res 48:23–29

    Article  CAS  PubMed  Google Scholar 

  • Han W-N, Hölscher C, Yuan L, Yang W, Wang X-H, Wu M-N, Qi J-S (2013) Liraglutide protects against amyloid-β protein-induced impairment of spatial learning and memory in rats. Neurobiol Aging 34:576–588

    Article  CAS  PubMed  Google Scholar 

  • Hatakeyama H, Akita H, Maruyama K, Suhara T, Harashima H (2004) Factors governing the in vivo tissue uptake of transferrin-coupled polyethylene glycol liposomes in vivo. Int J Pharm 281:25–33

    Article  CAS  PubMed  Google Scholar 

  • Hirschstein Z, Vanga GR, Wang G, Novakovic ZM, Grasso P (2020) MA-[D-Leu-4]-OB3, a small molecule synthetic peptide leptin mimetic, improves episodic memory, and reduces serum levels of tumor necrosis factor-alpha and neurodegeneration in mouse models of Type 1 and Type 2 Diabetes Mellitus. Biochim Biophys Acta Gen Subj 1864:129697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hölscher C (2012) Potential role of glucagon-like peptide-1 (GLP-1) in neuroprotection. CNS Drugs 26:871–882

    Article  PubMed  Google Scholar 

  • Holst JJ, Deacon CF, Vilsbøll T, Krarup T, Madsbad S (2008) Glucagon-like peptide-1, glucose homeostasis and diabetes. Trends Mol Med 14:161–168

    Article  CAS  PubMed  Google Scholar 

  • Holubova M, Blechova M, Kakonova A, Kunes J, Zelezna B, Maletinska L (2018) In vitro and in vivo characterization of novel stable peptidic ghrelin analogs: beneficial effects in the settings of lipopolysaccharide-induced anorexia in mice. J Pharmacol Exp Ther 366:422–432

    Article  CAS  PubMed  Google Scholar 

  • Huang J, Liu W, Doycheva DM, Gamdzyk M, Lu W, Tang J, Zhang JH (2019) Ghrelin attenuates oxidative stress and neuronal apoptosis via GHSR-1alpha/AMPK/Sirt1/PGC-1alpha/UCP2 pathway in a rat model of neonatal HIE. Free Radic Biol Med 141:322–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hultqvist G, Syvänen S, Fang XT, Lannfelt L, Sehlin D (2017) Bivalent brain shuttle increases antibody uptake by monovalent binding to the transferrin receptor. Theranostics 7:308–318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huwyler J, Wu D, Pardridge WM (1996) Brain drug delivery of small molecules using immunoliposomes. Proc Natl Acad Sci U S A 93:14164–14169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • James J, Mair S, Doll W, Sandefer E, Wurtman D, Maurer A, Deane AM, Harris MS (2020) The effects of ulimorelin, a ghrelin agonist, on liquid gastric emptying and colonic transit in humans. Neurogastroenterol Motil 32:e13784

    Article  CAS  PubMed  Google Scholar 

  • Jeon SG, Hong SB, Nam Y, Tae J, Yoo A, Song EJ, Kim KI, Lee D, Park J, Lee SM (2019) Ghrelin in Alzheimer’s disease: pathologic roles and therapeutic implications. Ageing Res Rev 55:100945

    Article  CAS  PubMed  Google Scholar 

  • Jeong Y-O, Shin SJ, Park JY, Ku BK, Song JS, Kim J-J, Jeon SG, Lee SM, Moon M (2018) MK-0677, a ghrelin agonist, alleviates amyloid beta-related pathology in 5XFAD mice, an animal model of Alzheimer’s disease. Int J Mol Sci 19:1800

    Article  PubMed Central  Google Scholar 

  • Johnston JM, Hu WT, Fardo DW, Greco SJ, Perry G, Montine TJ, Trojanowski JQ, Shaw LM, Ashford JW, Tezapsidis N, Alzheimer’s Disease Neuroimaging I (2014) Low plasma leptin in cognitively impaired ADNI subjects: gender differences and diagnostic and therapeutic potential. Curr Alzheimer Res 11:165–174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jolivalt CG, Lee CA, Beiswenger KK, Smith JL, Orlov M, Torrance MA, Masliah E (2008) Defective insulin signaling pathway and increased glycogen synthase kinase-3 activity in the brain of diabetic mice: parallels with Alzheimer’s disease and correction by insulin. J Neurosci Res 86:3265–3274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kamei N, Tanaka M, Choi H, Okada N, Ikeda T, Itokazu R, Takeda-Morishita M (2017) Effect of an enhanced nose-to-brain delivery of insulin on mild and progressive memory loss in the senescence-accelerated mouse. Mol Pharm 14:916–927

    Article  CAS  PubMed  Google Scholar 

  • Kamei N, Okada N, Ikeda T, Choi H, Fujiwara Y, Okumura H, Takeda-Morishita M (2018) Effective nose-to-brain delivery of exendin-4 via coadministration with cell-penetrating peptides for improving progressive cognitive dysfunction. Sci Rep 8:1–14

    Article  Google Scholar 

  • Kawai T, Sun B, Yoshino H, Feng D, Suzuki Y, Fukazawa M, Nagao S, Wainscott DB, Showalter AD, Droz BA, Kobilka TS, Coghlan MP, Willard FS, Kawabe Y, Kobilka BK, Sloop KW (2020) Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist. Proc Natl Acad Sci U S A 117:29959–29967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khafagy E-S, Kamei N, Fujiwara Y, Okumura H, Yuasa T, Kato M, Arime K, Nonomura A, Ogino H, Hirano S (2020) Systemic and brain delivery of leptin via intranasal coadministration with cell-penetrating peptides and its therapeutic potential for obesity. J Control Release 319:397–406

    Article  CAS  PubMed  Google Scholar 

  • Kim B-J, Zhou J, Martin B, Carlson OD, Maudsley S, Greig NH, Mattson MP, Ladenheim EE, Wustner J, Turner A (2010) Transferrin fusion technology: a novel approach to prolonging biological half-life of insulinotropic peptides. J Pharmacol Exp Ther 334:682–692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim S, Nam Y, Shin SJ, Park YH, Jeon SG, Kim JI, Kim MJ, Moon M (2020) The potential roles of ghrelin in metabolic syndrome and secondary symptoms of Alzheimer’s disease. Front Neurosci 14:583097

    Article  PubMed  PubMed Central  Google Scholar 

  • King MR, Anderson NJ, Deciu M, Guernsey LS, Cundiff M, Hajizadeh S, Jolivalt CG (2020) Insulin deficiency, but not resistance, exaggerates cognitive deficits in transgenic mice expressing human amyloid and tau proteins. Reversal by Exendin-4 treatment. J Neurosci Res 98:2357–2369

    Article  CAS  PubMed  Google Scholar 

  • Ko YT (2013) Nanoparticle-mediated delivery of oligonucleotides to the blood–brain barrier: in vitro and in situ brain perfusion studies on the uptake mechanisms. J Drug Target 21:866–873

    Article  CAS  PubMed  Google Scholar 

  • Kohno D, Nakata M, Maekawa F, Fujiwara K, Maejima Y, Kuramochi M, Shimazaki T, Okano H, Onaka T, Yada T (2007) Leptin suppresses ghrelin-induced activation of neuropeptide Y neurons in the arcuate nucleus via phosphatidylinositol 3-kinase- and phosphodiesterase 3-mediated pathway. Endocrinology 148:2251–2263

    Article  CAS  PubMed  Google Scholar 

  • Kołodziejski PA, Pruszyńska-Oszmałek E, Strowski MZ, Nowak KW (2017) Long-term obestatin treatment of mice type 2 diabetes increases insulin sensitivity and improves liver function. Endocrine 56:538–550

    Article  PubMed  Google Scholar 

  • Kunath N, Van Groen T, Allison DB, Kumar A, Dozier-Sharpe M, Kadish I (2015) Ghrelin agonist does not foster insulin resistance but improves cognition in an Alzheimer’s disease mouse model. Sci Rep 5:11452

    Article  PubMed  PubMed Central  Google Scholar 

  • Kuo Y-C, Ng I-W, Rajesh R (2021) Glutathione-and apolipoprotein E-grafted liposomes to regulate mitogen-activated protein kinases and rescue neurons in Alzheimer’s disease. Mater Sci Eng C Mater Biol Appl 127:112233

    Article  CAS  PubMed  Google Scholar 

  • Lee JY, Park T, Hong E, Amatya R, Park K-A, Park Y-H, Min KA, Jin M, Lee S, Hwang S (2020) Genetic engineering of novel super long-acting Exendin-4 chimeric protein for effective treatment of metabolic and cognitive complications of obesity. Biomaterials 257:120–250

    Article  Google Scholar 

  • Lieb W, Beiser AS, Vasan RS, Tan ZS, Au R, Harris TB, Roubenoff R, Auerbach S, Decarli C, Wolf PA, Seshadri S (2009) Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging. JAMA 302:2565–2572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Q, Zerbinatti CV, Zhang J, Hoe H-S, Wang B, Cole SL, Herz J, Muglia L, Bu G (2007) Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron 56:66–78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Z, Gan L, Wu T, Feng F, Luo D, Gu H, Liu S, Sun C (2016) Adiponectin reduces ER stress-induced apoptosis through PPAR α transcriptional regulation of ATF2 in mouse adipose. Cell Death Dis 7:e2487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu B, Liu J, Wang JG, Liu CL, Yan HJ (2020) AdipoRon improves cognitive dysfunction of Alzheimer’s disease and rescues impaired neural stem cell proliferation through AdipoR1/AMPK pathway. Exp Neurol 327:113249

    Article  CAS  PubMed  Google Scholar 

  • Lugar CW, Clay MP, Lindstrom TD, Woodson AL, Smiley D, Heiman ML, Dodge JA (2004) Synthesis and biological evaluation of an orally active ghrelin agonist that stimulates food consumption and adiposity in rats. Bioorg Med Chem Lett 14:5873–5876

    Article  CAS  PubMed  Google Scholar 

  • Lv M, Xue G, Cheng H, Meng P, Lian X, Hölscher C, Li D (2021) The GLP-1/GIP dual-receptor agonist DA5-CH inhibits the NF-κB inflammatory pathway in the MPTP mouse model of Parkinson’s disease more effectively than the GLP-1 single-receptor agonist NLY01. Brain Behav 11:2231

    Article  Google Scholar 

  • Ly PT, Wu Y, Zou H, Wang R, Zhou W, Kinoshita A, Zhang M, Yang Y, Cai F, Woodgett J, Song W (2013) Inhibition of GSK3beta-mediated BACE1 expression reduces Alzheimer-associated phenotypes. J Clin Invest 123:224–235

    Article  CAS  PubMed  Google Scholar 

  • Ma T, Du X, Pick JE, Sui G, Brownlee M, Klann E (2012) Glucagon-like peptide-1 cleavage product GLP-1 (9–36) amide rescues synaptic plasticity and memory deficits in Alzheimer’s disease model mice. J Neurosci 32:13701–13708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Macdonald PE, El-Kholy W, Riedel MJ, Salapatek AMF, Light PE, Wheeler MB (2002) The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion. Diabetes 51:S434–S442

    Article  CAS  PubMed  Google Scholar 

  • Malekizadeh Y, Holiday A, Redfearn D, Ainge JA, Doherty G, Harvey J (2017) A leptin fragment mirrors the cognitive enhancing and neuroprotective actions of leptin. Cereb Cortex 27:4769–4782

    Article  PubMed  Google Scholar 

  • Markoutsa E, Papadia K, Clemente C, Flores O, Antimisiaris SG (2012) Anti-Aβ-MAb and dually decorated nanoliposomes: effect of Aβ1-42 peptides on interaction with hCMEC/D3 cells. Eur J Pharm Biopharm 81:49–56

    Article  CAS  PubMed  Google Scholar 

  • Maskery M, Goulding EM, Gengler S, Melchiorsen JU, Rosenkilde MM, Hölscher C (2020) The dual GLP-1/GIP receptor agonist DA4-JC shows superior protective properties compared to the GLP-1 analogue liraglutide in the APP/PS1 mouse model of Alzheimer’s disease. Am J Alzheimers Dis Other Demen 35:1–11

    Article  Google Scholar 

  • Mcclean PL, Parthsarathy V, Faivre E, Hölscher C (2011) The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease. J Neurosci 31:6587–6594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mcnay EC, Ong CT, Mccrimmon RJ, Cresswell J, Bogan JS, Sherwin RS (2010) Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance. Neurobiol Learn Mem 93:546–553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meng T, Cao Q, Lei P, Bush AI, Xiang Q, Su Z, He X, Rogers JT, Chiu M, Zhang Q (2017) Tat-haFGF14–154 upregulates ADAM10 to attenuate the Alzheimer phenotype of APP/PS1 mice through the PI3K-CREB-IRE1α/XBP1 pathway. Mol Ther Nucleic Acids 7:439–452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mercer JG, Hoggard N, Williams LM, Lawrence CB, Hannah LT, Trayhurn P (1996) Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization. FEBS Lett 387:113–116

    Article  CAS  PubMed  Google Scholar 

  • Miao W, Jiang L, Xu F, Lyu J, Jiang X, He M, Liu Y, Yang T, Leak RK, Stetler RA, Chen J, Hu X (2021) Adiponectin ameliorates hypoperfusive cognitive deficits by boosting a neuroprotective microglial response. Prog Neurobiol 205:102125

    Article  CAS  PubMed  Google Scholar 

  • Miele M, Costantini S, Colonna G (2011) Structural and functional similarities between osmotin from Nicotiana tabacum seeds and human adiponectin. PLoS ONE 6:e16690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Minalyan A, Gabrielyan L, Pietra C, Tache Y, Wang L (2019) Multiple beneficial effects of ghrelin agonist, HM01 on homeostasis alterations in 6-hydroxydopamine model of Parkinson’s disease in male rats. Front Integr Neurosci 13:13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mohamed SH, Shahat AA, Mohamed MR, Khalil WK, Salem AM, Farrag ARH, Ahmed HH (2021) Camellia sinesis leaves extract ameliorates high fat diet-induced nonalcoholic steatohepatitis in rats: analysis of potential mechanisms. J Pharm Investig 51:183–197

    Article  CAS  Google Scholar 

  • Moult PR, Harvey J (2008) Hormonal regulation of hippocampal dendritic morphology and synaptic plasticity. Cell Adh Migr 2:269–275

    Article  PubMed  PubMed Central  Google Scholar 

  • Mourtas S, Lazar AN, Markoutsa E, Duyckaerts C, Antimisiaris SG (2014) Multifunctional nanoliposomes with curcumin–lipid derivative and brain targeting functionality with potential applications for Alzheimer disease. Eur J Med Chem 80:175–183

    Article  CAS  PubMed  Google Scholar 

  • Nasir Abbas Bukhari S, Jantan I (2015) Synthetic curcumin analogs as inhibitors of β-amyloid peptide aggregation: potential therapeutic and diagnostic agents for Alzheimer’s disease. Mini Rev Med Chem 15:1110–1121

    Article  Google Scholar 

  • Nazer B, Hong S, Selkoe DJ (2008) LRP promotes endocytosis and degradation, but not transcytosis, of the amyloid-β peptide in a blood–brain barrier in vitro model. Neurobiol Dis 30:94–102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nehra G, Bauer B, Hartz AM (2022) Blood-brain barrier leakage in Alzheimer’s disease: from discovery to clinical relevance. Pharmacol Ther 234:108–119

    Article  Google Scholar 

  • Neves AR, Queiroz JF, SaC L, Reis S (2017) Apo E-functionalization of solid lipid nanoparticles enhances brain drug delivery: uptake mechanism and transport pathways. Bioconjug Chem 28:995–1004

    Article  CAS  PubMed  Google Scholar 

  • Ng RC-L, Chan K-H (2017) Potential neuroprotective effects of adiponectin in Alzheimer’s disease. Int J Mol Sci 18:592

    Article  Google Scholar 

  • Ng RC-L, Cheng O-Y, Jian M, Kwan JS-C, Ho PW-L, Cheng KK-Y, Yeung PKK, Zhou LL, Hoo RL-C, Chung SK (2016) Chronic adiponectin deficiency leads to Alzheimer’s disease-like cognitive impairments and pathologies through AMPK inactivation and cerebral insulin resistance in aged mice. Mol Neurodegener 11:71

    Article  PubMed  PubMed Central  Google Scholar 

  • Ng RC-L, Jian M, Ma OK-F, Bunting M, Kwan JS-C, Zhou G-J, Senthilkumar K, Iyaswamy A, Chan P-K, Li M (2020) Chronic oral administration of adipoRon reverses cognitive impairments and ameliorates neuropathology in an Alzheimer’s disease mouse model. Mol Psychiatry 26:5669–5689

    Article  PubMed  Google Scholar 

  • Novakovic ZM, Leinung MC, Lee DW, Grasso P (2010) Oral delivery of mouse [d-Leu-4]-OB3, a synthetic peptide amide with leptin-like activity, in male C57BL/6J wild-type and ob/ob mice: effects on energy balance, glycaemic control and serum osteocalcin levels. Diabetes Obes Metab 12:532–539

    Article  CAS  PubMed  Google Scholar 

  • Okada-Iwabu M, Yamauchi T, Iwabu M, Honma T, Hamagami K, Matsuda K, Yamaguchi M, Tanabe H, Kimura-Someya T, Shirouzu M, Ogata H, Tokuyama K, Ueki K, Nagano T, Tanaka A, Yokoyama S, Kadowaki T (2013) A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. Nature 503:493–499

    Article  CAS  PubMed  Google Scholar 

  • Omori N, Maruyama K, Jin G, Wang S, Hamakawa Y, Sato K, Nagano I, Shoji M, Abe K (2003) Targeting of post-ischemic cerebral endothelium in rat by liposomes bearing polyethylene glycol-coupled transferrin. Neurol Res 25:275–279

    Article  CAS  PubMed  Google Scholar 

  • Oomura Y, Hori N, Shiraishi T, Fukunaga K, Takeda H, Tsuji M, Matsumiya T, Ishibashi M, Aou S, Li XL, Kohno D, Uramura K, Sougawa H, Yada T, Wayner MJ, Sasaki K (2006) Leptin facilitates learning and memory performance and enhances hippocampal CA1 long-term potentiation and CaMK II phosphorylation in rats. Peptides 27:2738–2749

    Article  CAS  PubMed  Google Scholar 

  • Papadia K, Giannou AD, Markoutsa E, Bigot C, Vanhoute G, Mourtas S, Van Der Linded A, Stathopoulos GT, Antimisiaris SG (2017) Multifunctional LUV liposomes decorated for BBB and amyloid targeting-B. In vivo brain targeting potential in wild-type and APP/PS1 mice. Eur J Pharm Sci 102:180–187

    Article  CAS  PubMed  Google Scholar 

  • Pardridge WM (2002) Drug and gene targeting to the brain with molecular Trojan horses. Nat Rev Drug Discov 1:131–139

    Article  CAS  PubMed  Google Scholar 

  • Pardridge WM (2003) Blood-brain barrier drug targeting: the future of brain drug development. Mol Interv 3:90–105

    Article  CAS  PubMed  Google Scholar 

  • Pardridge WM (2020a) Treatment of Alzheimer’s disease and blood–brain barrier drug delivery. Pharmaceuticals 13:394

    Article  CAS  PubMed Central  Google Scholar 

  • Pardridge WM (2020b) Blood-brain barrier and delivery of protein and gene therapeutics to brain. Front Aging Neurosci 11:373

    Article  PubMed  PubMed Central  Google Scholar 

  • Pardridge WM, Kang Y-S, Buciak JL, Yang J (1995) Human insulin receptor monoclonal antibody undergoes high affinity binding to human brain capillaries in vitro and rapid transcytosis through the blood–brain barrier in vivo in the primate. Pharm Res 12:807–816

    Article  CAS  PubMed  Google Scholar 

  • Park K-A, Jin Z, Lee JY, An HS, Choi EB, Kim KE, Shin HJ, Jeong E, Min KA, Shin MC (2020) Long-lasting exendin-4 fusion protein improves memory deficits in high-fat diet/streptozotocin-induced diabetic mice. Pharmaceutics 12:159

    Article  CAS  PubMed Central  Google Scholar 

  • Perry TA, Greig NH (2004) A new Alzheimer’s disease interventive strategy: GLP-1. Curr Drug Targets 5:565–571

    Article  CAS  PubMed  Google Scholar 

  • Perry T, Haughey NJ, Mattson MP, Egan JM, Greig NH (2002) Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4. J Pharmacol Exp Ther 302:881–888

    Article  CAS  PubMed  Google Scholar 

  • Perry T, Lahiri DK, Sambamurti K, Chen D, Mattson MP, Egan JM, Greig NH (2003) Glucagon-like peptide-1 decreases endogenous amyloid-β peptide (Aβ) levels and protects hippocampal neurons from death induced by Aβ and iron. J Neurosci Res 72:603–612

    Article  CAS  PubMed  Google Scholar 

  • Petri M, Singh I, Baker C, Underkofler C, Rasouli N (2021) Diabetic gastroparesis: an overview of pathogenesis, clinical presentation and novel therapies, with a focus on ghrelin receptor agonists. J Diabetes Complications 35:107–733

    Article  Google Scholar 

  • Pflanzner T, Janko MC, André-Dohmen B, Reuss S, Weggen S, Roebroek AJ, Kuhlmann CR, Pietrzik CU (2011) LRP1 mediates bidirectional transcytosis of amyloid-β across the blood-brain barrier. Neurobiol Aging 32:2323.e1-2323.e11

    Article  CAS  Google Scholar 

  • Popelova A, Kakonova A, Hruba L, Kunes J, Maletinska L, Zelezna B (2018) Potential neuroprotective and anti-apoptotic properties of a long-lasting stable analog of ghrelin: an in vitro study using SH-SY5Y cells. Physiol Res 67:339–346

    Article  CAS  PubMed  Google Scholar 

  • Pousti F, Ahmadi R, Mirahmadi F, Hosseinmardi N, Rohampour K (2018) Adiponectin modulates synaptic plasticity in hippocampal dentate gyrus. Neurosci Lett 662:227–232

    Article  CAS  PubMed  Google Scholar 

  • Pradhan G, Wu C-S, Lee JH, Kanikarla P, Guo S, Yechoor VK, Samson SL, Sun Y (2017) Obestatin stimulates glucose-induced insulin secretion through ghrelin receptor GHS-R. Sci Rep 7:979

    Article  PubMed  PubMed Central  Google Scholar 

  • Ramanathan A, Nelson AR, Sagare AP, Zlokovic BV (2015) Impaired vascular-mediated clearance of brain amyloid beta in Alzheimer’s disease: the role, regulation and restoration of LRP1. Front Aging Neurosci 7:136

    Article  PubMed  PubMed Central  Google Scholar 

  • Rao KS, Reddy MK, Horning JL, Labhasetwar V (2008) TAT-conjugated nanoparticles for the CNS delivery of anti-HIV drugs. Biomaterials 29:4429–4438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Regina A, Demeule M, Tripathy S, Lord-Dufour S, Currie J-C, Iddir M, Annabi B, Castaigne J-P, Lachowicz JE (2015) ANG4043, a novel brain-penetrant peptide–mAb conjugate, is efficacious against HER2-positive intracranial tumors in mice. Mol Cancer Ther 14:129–140

    Article  CAS  PubMed  Google Scholar 

  • Resende R, Ferreira-Marques M, Moreira P, Coimbra JR, Baptista SJ, Isidoro C, Salvador JA, Dinis TC, Pereira CF, Santos AE (2020) New BACE1 chimeric peptide inhibitors selectively prevent AβPP-β cleavage decreasing amyloid-β production and accumulation in Alzheimer’s disease models. J Alzheimers Dis 76:1317–1337

    Article  CAS  PubMed  Google Scholar 

  • Rhea EM, Banks WA (2019) Role of the blood-brain barrier in central nervous system insulin resistance. Front Neurosci 13:521

    Article  PubMed  PubMed Central  Google Scholar 

  • Rodrigues BDS, Kanekiyo T, Singh J (2020) Nerve growth factor gene delivery across the blood-brain barrier to reduce beta amyloid accumulation in AD mice. Mol Pharm 17:2054–2063

    Article  CAS  PubMed  Google Scholar 

  • Roujeau C, Jockers R, Dam J (2014) New pharmacological perspectives for the leptin receptor in the treatment of obesity. Front Endocrinol 5:167

    Article  Google Scholar 

  • Rozhavskaya-Arena M, Lee DW, Leinung MC, Grasso P (2000) Design of a synthetic leptin agonist: effects on energy balance, glucose homeostasis, and thermoregulation. Endocrinology 141:2501–2507

    Article  CAS  PubMed  Google Scholar 

  • Saito Y, Buciak J, Yang J, Pardridge WM (1995) Vector-mediated delivery of 125I-labeled beta-amyloid peptide A beta 1–40 through the blood-brain barrier and binding to Alzheimer disease amyloid of the A beta 1–40/vector complex. Proc Natl Acad Sci U S A 92:10227–10231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Salles GN, Calió ML, Hölscher C, Pacheco-Soares C, Porcionatto M, Lobo AO (2020) Neuroprotective and restorative properties of the GLP-1/GIP dual agonist DA-JC1 compared with a GLP-1 single agonist in Alzheimer’s disease. Neuropharmacology 162:107813

    Article  CAS  PubMed  Google Scholar 

  • Saraiva C, Praça C, Ferreira R, Santos T, Ferreira L, Bernardino L (2016) Nanoparticle-mediated brain drug delivery: overcoming blood–brain barrier to treat neurodegenerative diseases. J Control Release 235:34–47

    Article  CAS  PubMed  Google Scholar 

  • Sarko D, Beijer B, Garcia Boy R, Nothelfer E-M, Leotta K, Eisenhut M, Altmann A, Haberkorn U, Mier W (2010) The pharmacokinetics of cell-penetrating peptides. Mol Pharm 7:2224–2231

    Article  CAS  PubMed  Google Scholar 

  • Savioz A, Charnay Y, Huguenin C, Graviou C, Greggio B, Bouras C (1997) Expression of leptin receptor mRNA (long form splice variant) in the human cerebellum. NeuroReport 8:3123–3126

    Article  CAS  PubMed  Google Scholar 

  • Saxena AR, Gorman DN, Esquejo RM, Bergman A, Chidsey K, Buckeridge C, Griffith DA, Kim AM (2021) Danuglipron (PF-06882961) in type 2 diabetes: a randomized, placebo-controlled, multiple ascending-dose phase 1 trial. Nat Med 27:1079–1087

    Article  CAS  PubMed  Google Scholar 

  • Shah B (2021) Microemulsion as a promising carrier for nose to brain delivery: journey since last decade. J Pharm Investig 51:611–634

    Article  Google Scholar 

  • Shah SA, Yoon GH, Chung SS, Abid MN, Kim TH, Lee HY, Kim MO (2017) Novel osmotin inhibits SREBP2 via the AdipoR1/AMPK/SIRT1 pathway to improve Alzheimer’s disease neuropathological deficits. Mol Psychiatry 22:407–416

    Article  CAS  PubMed  Google Scholar 

  • Shao K, Huang R, Li J, Han L, Ye L, Lou J, Jiang C (2010) Angiopep-2 modified PE-PEG based polymeric micelles for amphotericin B delivery targeted to the brain. J Control Release 147:118–126

    Article  CAS  PubMed  Google Scholar 

  • Shen J, Zhan C, Xie C, Meng Q, Gu B, Li C, Zhang Y, Lu W (2011) Poly (ethylene glycol)-block-poly (D, L-lactide acid) micelles anchored with angiopep-2 for brain-targeting delivery. J Drug Target 19:197–203

    Article  CAS  PubMed  Google Scholar 

  • Shi L, Du X, Jiang H, Xie J (2017a) Ghrelin and neurodegenerative disorders-a review. Mol Neurobiol 54:1144–1155

    Article  CAS  PubMed  Google Scholar 

  • Shi L, Zhang Z, Li L, Hölscher C (2017b) A novel dual GLP-1/GIP receptor agonist alleviates cognitive decline by re-sensitizing insulin signaling in the Alzheimer ICV. STZ Rat Model Behav Brain Res 327:65–74

    Article  CAS  PubMed  Google Scholar 

  • Shibata N, Ohnuma T, Kuerban B, Komatsu M, Arai H (2011) Genetic association between ghrelin polymorphisms and Alzheimer’s disease in a Japanese population. Dement Geriatr Cogn Disord 32:178–181

    Article  CAS  PubMed  Google Scholar 

  • Shin MC, Zhang J, Min KA, Lee K, Byun Y, David AE, He H, Yang VC (2014) Cell-penetrating peptides: achievements and challenges in application for cancer treatment. J Biomed Mater Res A 102:575–587

    Article  PubMed  Google Scholar 

  • Singh VK, Subudhi BB (2016) Development and characterization of lysine-methotrexate conjugate for enhanced brain delivery. Drug Deliv 23:2327–2337

    Article  CAS  PubMed  Google Scholar 

  • Song J, Kang S, Kim E, Kim C, Song H, Lee J (2015) Adiponectin receptor-mediated signaling ameliorates cerebral cell damage and regulates the neurogenesis of neural stem cells at high glucose concentrations: an in vivo and in vitro study. Cell Death Dis 6:e1844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sumbria RK, Hui EK-W, Lu JZ, Boado RJ, Pardridge WM (2013) Disaggregation of amyloid plaque in brain of Alzheimer’s disease transgenic mice with daily subcutaneous administration of a tetravalent bispecific antibody that targets the transferrin receptor and the Abeta amyloid peptide. Mol Pharm 10:3507–3513

    Article  CAS  PubMed  Google Scholar 

  • Tai J, Liu W, Li Y, Li L, Holscher C (2018) Neuroprotective effects of a triple GLP-1/GIP/glucagon receptor agonist in the APP/PS1 transgenic mouse model of Alzheimer’s disease. Brain Res 1678:64–74

    Article  CAS  PubMed  Google Scholar 

  • Takahashi M, Arita Y, Yamagata K, Matsukawa Y, Okutomi K, Horie M, Shimomura I, Hotta K, Kuriyama H, Kihara S (2000) Genomic structure and mutations in adipose-specific gene, adiponectin. Int J Obes Relat Metab Disord 24:861–868

    Article  CAS  PubMed  Google Scholar 

  • Thundyil J, Pavlovski D, Sobey CG, Arumugam TV (2012) Adiponectin receptor signalling in the brain. Br J Pharmacol 165:313–327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tian J, Wang T, Wang Q, Guo L, Du H (2019) MK0677, a ghrelin mimetic, improves neurogenesis but fails to prevent hippocampal lesions in a mouse model of Alzheimer’s disease pathology. J Alzheimers Dis 72:467–478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tong JQ, Zhang J, Hao M, Yang J, Han YF, Liu XJ, Shi H, Wu MN, Liu QS, Qi JS (2015) Leptin attenuates the detrimental effects of beta-amyloid on spatial memory and hippocampal later-phase long term potentiation in rats. Horm Behav 73:125–130

    Article  CAS  PubMed  Google Scholar 

  • Topal GR, Mészáros M, Porkoláb G, Szecskó A, Polgár TF, Siklós L, Deli MA, Veszelka S, Bozkir A (2021) ApoE-targeting increases the transfer of solid lipid nanoparticles with donepezil cargo across a culture model of the blood–brain barrier. Pharmaceutics 13:38

    Article  CAS  Google Scholar 

  • Tortorella S, Karagiannis TC (2014) Transferrin receptor-mediated endocytosis: a useful target for cancer therapy. J Membr Biol 247:291–307

    Article  CAS  PubMed  Google Scholar 

  • Tramutola A, Arena A, Cini C, Butterfield DA, Barone E (2017) Modulation of GLP-1 signaling as a novel therapeutic approach in the treatment of Alzheimer’s disease pathology. Expert Rev Neurother 17:59–75

    Article  CAS  PubMed  Google Scholar 

  • Vadini F, Simeone PG, Boccatonda A, Guagnano MT, Liani R, Tripaldi R, Di Castelnuovo A, Cipollone F, Consoli A, Santilli F (2020) Liraglutide improves memory in obese patients with prediabetes or early type 2 diabetes: a randomized, controlled study. Int J Obes 44:1254–1263

    Article  CAS  Google Scholar 

  • Valcarce C, Dunn I, Freeman JL (2019) Effects of the oral, small molecule GLP-1R agonist TTP273 on patients with stage 2 hypertension: results from a post hoc analysis of the phase 2 logra study. Diabetes 68:1015

    Article  Google Scholar 

  • Wang C, Mao X, Wang L, Liu M, Wetzel MD, Guan KL, Dong LQ, Liu F (2007) Adiponectin sensitizes insulin signaling by reducing p70 S6 kinase-mediated serine phosphorylation of IRS-1. J Biol Chem 282:7991–7996

    Article  CAS  PubMed  Google Scholar 

  • Wang A, Anderson BM, Novakovic ZM, Grasso P (2018) [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3, small molecule synthetic peptide leptin mimetics, improve glycemic control in diet-induced obese (DIO) mice. Peptides 101:51–59

    Article  CAS  PubMed  Google Scholar 

  • Watanabe T (2020) Therapeutic properties of the new phytochemical osmotin for preventing atherosclerosis. Vessel Plus 4:4

    CAS  Google Scholar 

  • Willard FS, Ho JD, Sloop KW (2020) Discovery and pharmacology of the covalent GLP-1 receptor (GLP-1R) allosteric modulator BETP: A novel tool to probe GLP-1R pharmacology. Adv Pharmacol 88:173–191

    Article  CAS  PubMed  Google Scholar 

  • Wu D, Yang J, Pardridge WM (1997) Drug targeting of a peptide radiopharmaceutical through the primate blood-brain barrier in vivo with a monoclonal antibody to the human insulin receptor. J Clin Invest 100:1804–1812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xia H, Gao X, Gu G, Liu Z, Hu Q, Tu Y, Song Q, Yao L, Pang Z, Jiang X (2012) Penetratin-functionalized PEG–PLA nanoparticles for brain drug delivery. Int J Pharm 436:840–850

    Article  CAS  PubMed  Google Scholar 

  • Yamauchi T, Nio Y, Maki T, Kobayashi M, Takazawa T, Iwabu M, Okada-Iwabu M, Kawamoto S, Kubota N, Kubota T, Ito Y, Kamon J, Tsuchida A, Kumagai K, Kozono H, Hada Y, Ogata H, Tokuyama K, Tsunoda M, Ide T, Murakami K, Awazawa M, Takamoto I, Froguel P, Hara K, Tobe K, Nagai R, Ueki K, Kadowaki T (2007) Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med 13:332–339

    Article  CAS  PubMed  Google Scholar 

  • Yemisci M, Caban S, Gursoy-Ozdemir Y, Lule S, Novoa-Carballal R, Riguera R, Fernandez-Megia E, Andrieux K, Couvreur P, Capan Y (2015) Systemically administered brain-targeted nanoparticles transport peptides across the blood–brain barrier and provide neuroprotection. J Cereb Blood Flow Metab 35:469–475

    Article  CAS  PubMed  Google Scholar 

  • Yin H, Tian S, Huang R, Cai R, Guo D, Lin H, Wang J, Wang S (2018) Low plasma leptin and high soluble leptin receptor levels are associated with mild cognitive impairment in type 2 diabetic patients. Front Aging Neurosci 10:132

    Article  PubMed  PubMed Central  Google Scholar 

  • Yoon G, Shah SA, Ali T, Kim MO (2018) The adiponectin homolog osmotin enhances neurite outgrowth and synaptic complexity via AdipoR1/NgR1 signaling in Alzheimer’s disease. Mol Neurobiol 55:6673–6686

    Article  CAS  PubMed  Google Scholar 

  • Yu YJ, Zhang Y, Kenrick M, Hoyte K, Luk W, Lu Y, Atwal J, Elliott JM, Prabhu S, Watts RJ (2011) Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. Sci Transl Med 3:84ra44

    Article  PubMed  Google Scholar 

  • Zhang Y, Schlachetzki F, Zhang Y-F, Boado RJ, Pardridge WM (2004) Normalization of striatal tyrosine hydroxylase and reversal of motor impairment in experimental parkinsonism with intravenous nonviral gene therapy and a brain-specific promoter. Hum Gene Ther 15:339–350

    Article  CAS  PubMed  Google Scholar 

  • Zhang JV, Ren P-G, Avsian-Kretchmer O, Luo C-W, Rauch R, Klein C, Hsueh AJ (2005) Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin’s effects on food intake. Science 310:996–999

    Article  CAS  PubMed  Google Scholar 

  • Zhang C, Su Z, Zhao B, Qu Q, Tan Y, Cai L, Li X (2010) Tat-modified leptin is more accessible to hypothalamus through brain-blood barrier with a significant inhibition of body-weight gain in high-fat-diet fed mice. Exp Clin Endocrinol Diabetes 118:31–37

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Yi T, Cheng S, Zhang S (2020) Glucagon-like peptide-1 receptor agonist Exendin-4 improves neurological outcomes by attenuating TBI-induced inflammatory responses and MAPK activation in rats. Int Immunopharmacol 86:106715

    Article  CAS  PubMed  Google Scholar 

  • Zhao W-Q, Chen H, Quon MJ, Alkon DL (2004) Insulin and the insulin receptor in experimental models of learning and memory. Eur J Pharmacol 490:71–81

    Article  CAS  PubMed  Google Scholar 

  • Zhao P, Liang Y-L, Belousoff MJ, Deganutti G, Fletcher MM, Willard FS, Bell MG, Christe ME, Sloop KW, Inoue A (2020) Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin’s effects on food intake. Nature 577:432–436

    Article  CAS  PubMed  Google Scholar 

  • Zhou Q-H, Fu A, Boado RJ, Hui EK-W, Lu JZ, Pardridge WM (2011) Receptor-mediated abeta amyloid antibody targeting to Alzheimer’s disease mouse brain. Mol Pharm 8:280–285

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was financially supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT; Ministry of Science and ICT) (NRF-2021R1F1A1058214 to Shin MC, NRF-2021R1F1A1064206 to Min KA).

Author information

Authors and Affiliations

  1. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju Daero, Jinju, Gyeongnam, 52828, Republic of Korea

    Reeju Amatya & Meong Cheol Shin

  2. College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, 197 Injero, Gimhae, Gyeongnam, 50834, Republic of Korea

    Kyoung Ah Min

Authors
  1. Reeju Amatya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kyoung Ah Min
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Meong Cheol Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Kyoung Ah Min or Meong Cheol Shin.

Ethics declarations

Conflict of interest

All authors (R. Amatya, K.A. Min, M.C. Shin) declare that they have no conflicts of interest.

Statement of human and animal rights

This article does not contain any studies with human and animal subjects performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Amatya, R., Min, K.A. & Shin, M.C. A review of glucoregulatory hormones potentially applicable to the treatment of Alzheimer’s disease: mechanism and brain delivery. J. Pharm. Investig. 52, 195–216 (2022). https://doi.org/10.1007/s40005-022-00566-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40005-022-00566-y

Keywords

Search

Navigation