Restricted accessResearch articleFirst published online 2025-1
Intranasal long R3 insulin-like growth factor-1 treatment promotes amyloid plaque remodeling in cerebral cortex but fails to preserve cognitive function in male 5XFAD mice
Insulin-like growth factor-1 (IGF-1) promotes neurogenesis, cell survival, and glial function, making it a promising candidate therapy in Alzheimer's disease (AD).
Objective
Long arginine 3-IGF-1 (LR3-IGF-1) is a potent IGF-1 analogue. We sought to determine whether intranasal (IN) LR3 treatment would delay cognitive decline and pathology in 5XFAD mice.
Methods
Wildtype and 5XFAD male mice were treated for 7 months (3–10 months of age), with IN LR3-IGF-1 or IN Vehicle (Veh) (n = 19–27 mice/group). Behavior, memory, and brain imaging were assessed at 8–9 months of age and tissues collected at 10 months. A comprehensive amyloid-β (Aβ) profile and other pathologic features were conducted and supportive in vitro stimulation studies in BV-2 microglial cells were also performed.
Results
In male 5XFAD mice, IN LR3-IGF-1 treatment improved body composition, but did not significantly alter cognitive symptoms, as assessed by multiple assays. In cortex, LR3 treatment improved some facets of pathology, including a reduction in filamentous plaques, and increase in inert plaques, corresponding with a reduction in low molecular weight Aβ oligomers. In vitro, uptake of Aβ1–42 peptide by BV2 cells was enhanced by LR3-IGF-1, which was also found to promote gene pathways implicated in actin remodeling and endocytosis.
Conclusions
LR3 promotes favorable effects on Aβ plaque remodeling in cortex of male 5XFAD mice but fails to preserve aspects of behavior or memory. While these data do not support LR3 as a monotherapy per se, they do warrant further investigation into its potential for combinatorial formulations aimed at targeting the complexity of AD.
MayeuxRSternY. Epidemiology of Alzheimer disease. Cold Spring Harb Perspect Med2012; 2: 20120801.
2.
LleóAGreenbergSMGrowdonJH. Current pharmacotherapy for Alzheimer's disease. Ann Rev Med2006; 57: 513–533.
3.
MusiekESGomez-IslaTHoltzmanDM. Aducanumab for Alzheimer disease: the amyloid hypothesis moves from bench to bedside. J Clin Invest2021; 131: e154889.
4.
CraftSRamanRChowTW, et al.Safety, efficacy, and feasibility of intranasal insulin for the treatment of mild cognitive impairment and Alzheimer disease dementia: a randomized clinical trial. JAMA Neurol2020; 77: 1099–1109.
5.
CarroETrejoJLGerberA, et al.Therapeutic actions of insulin-like growth factor I on APP/PS2 mice with severe brain amyloidosis. Neurobiol Aging2006; 27: 1250–1257.
6.
CarroETrejoJLGomez-IslaT, et al.Serum insulin-like growth factor I regulates brain amyloid-beta levels. Nat Med2002; 8: 1390–1397.
7.
LanzTASalattoCTSemproniAR, et al.Peripheral elevation of IGF-1 fails to alter abeta clearance in multiple in vivo models. Biochem Pharmacol2008; 75: 1093–1103.
8.
Trueba-SáizACavadaCFernandezAM, et al.Loss of serum IGF-I input to the brain as an early biomarker of disease onset in Alzheimer mice. Transl Psychiatry2013; 3: e330–e330.
9.
SevignyJJRyanJMvan DyckCH, et al.Growth hormone secretagogue MK-677: no clinical effect on AD progression in a randomized trial. Neurology2008; 71: 1702–1708.
10.
BakerLDBarsnessSMBorsonS, et al.Effects of growth hormone–releasing hormone on cognitive function in adults with mild cognitive impairment and healthy older adults: results of a controlled trial. Arch Neurol2012; 69: 1420–1429.
11.
ZhangWBYeKBarzilaiN, et al.The antagonistic pleiotropy of insulin-like growth factor 1. Aging Cell2021; 20: e13443.
12.
GubbiSQuipildorGFBarzilaiN, et al.40 YEARS of IGF1: IGF1: the Jekyll and Hyde of the aging brain. J Mol Endocrinol2018; 61: T171–T185.
13.
VitaleGPellegrinoGVolleryM, et al.Role of IGF-1 system in the modulation of longevity: controversies and new insights from a centenarians’ perspective. Front Endocrinol (Lausanne)2019; 10: 27.
14.
JunnilaRKListEOBerrymanDE, et al.The GH/IGF-1 axis in ageing and longevity. Nat Rev Endocrinol2013; 9: 366–376.
15.
SunLYAl-RegaieyKMasternakMM, et al.Local expression of GH and IGF-1 in the hippocampus of GH-deficient long-lived mice. Neurobiol Aging2005; 26: 929–937.
16.
TothPTarantiniSAshpoleNM, et al.IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging. Aging Cell2015; 14: 1034–1044.
17.
TarantiniSBalasubramanianPYabluchanskiyA, et al.IGF1R Signaling regulates astrocyte-mediated neurovascular coupling in mice: implications for brain aging. GeroScience2021; 43: 901–911.
18.
FulopGARamirez-PerezFIKissT, et al.IGF-1 deficiency promotes pathological remodeling of cerebral arteries: a potential mechanism contributing to the pathogenesis of intracerebral hemorrhages in aging. J Gerontol A Biol Sci Med Sci2019; 74: 446–454.
19.
PharaohGOwenDYeganehA, et al.Disparate central and peripheral effects of circulating IGF-1 deficiency on tissue mitochondrial function. Mol Neurobiol2020; 57: 1317–1331.
20.
RamseyMMWeinerJLMooreTP, et al.Growth hormone treatment attenuates age-related changes in hippocampal short-term plasticity and spatial learning. Neuroscience2004; 129: 119–127.
21.
LichtenwalnerRJForbesMEBennettSA, et al.Intracerebroventricular infusion of insulin-like growth factor-I ameliorates the age-related decline in hippocampal neurogenesis. Neuroscience2001; 107: 603–613.
22.
SonntagWELynchCThorntonP, et al.The effects of growth hormone and IGF-1 deficiency on cerebrovascular and brain ageing. J Anat2000; 197: 575–585.
Farias QuipildorGEMaoKHuZ, et al.Central IGF-1 protects against features of cognitive and sensorimotor decline with aging in male mice. Geroscience2019; 41: 185–208.
25.
ThorneRGPronkGJPadmanabhanV, et al.Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience2004; 127: 481–496.
26.
LopesCRibeiroMDuarteAI, et al.IGF-1 intranasal administration rescues Huntington's disease phenotypes in YAC128 mice. Mol Neurobiol2014; 49: 1126–1142.
27.
LinSFanL-WRhodesPG, et al.Intranasal administration of IGF-1 attenuates hypoxic-ischemic brain injury in neonatal rats. Exp Neurol2009; 217: 361–370.
28.
LiuX-FFawcettJRThorneRG, et al.Non-invasive intranasal insulin-like growth factor-I reduces infarct volume and improves neurologic function in rats following middle cerebral artery occlusion. Neurosci Lett2001; 308: 91–94.
29.
LekicTFloresJKlebeD, et al.Intranasal IGF-1 reduced rat pup germinal matrix hemorrhage. Acta Neurochir Suppl2016; 121: 209–212.
30.
CaiZFanLWLinS, et al.Intranasal administration of insulin-like growth factor-1 protects against lipopolysaccharide-induced injury in the developing rat brain. Neuroscience2011; 194: 195–207.
31.
TienL-TLeeY-JPangY, et al.Neuroprotective effects of intranasal IGF-1 against neonatal lipopolysaccharide-induced neurobehavioral deficits and neuronal inflammation in the substantia nigra and locus coeruleus of juvenile rats. Dev Neurosci2017; 39: 443–459.
32.
LaajokiLGFrancisGLWallaceJC, et al.Solution structure and backbone dynamics of long-[arg(3)]insulin-like growth factor-I. J Biol Chem2000; 275: 10009–10015.
33.
KingRWellsJRKriegP, et al.Production and characterization of recombinant insulin-like growth factor-I (IGF-I) and potent analogues of IGF-I, with Gly or Arg substituted for Glu3, following their expression in Escherichia coli as fusion proteins. J Mol Endocrinol1992; 8: 29–41.
34.
HansonLRFineJMSvitakAL, et al.Intranasal administration of CNS therapeutics to awake mice. J Vis Exp2013; 74: 4440.
35.
DarvasMMukherjeeKLeeA, et al.A novel one-day learning procedure for mice. Curr Protoc Mouse Biol2020; 10: e68.
36.
KraeuterAKGuestPCSarnyaiZ. The Y-maze for assessment of spatial working and reference memory in mice. Methods Mol Biol2019; 1916: 105–111.
37.
CanADaoDTAradM, et al.The mouse forced swim test. J Vis Exp2012; 59: e3638.
38.
BogdanovaOVKanekarSD'AnciKE, et al.Factors influencing behavior in the forced swim test. Physiol Behav2013; 118: 227–239.
39.
YangMCrawleyJN. Simple behavioral assessment of mouse olfaction. Curr Protoc Neurosci2009; Chapter 8: Unit 8.24.
40.
MerhebECuiMHDuBoisJC, et al.Defective myelination in an RNA polymerase III mutant leukodystrophic mouse. Proc Natl Acad Sci U S A2021; 118: e2024378118.
41.
KimSGUgurbilK. Comparison of blood oxygenation and cerebral blood flow effects in fMRI: estimation of relative oxygen consumption change. Magn Reson Med1997; 38: 59–65.
42.
DorrAELerchJPSpringS, et al.High resolution three-dimensional brain atlas using an average magnetic resonance image of 40 adult C57Bl/6J mice. Neuroimage2008; 42: 60–69.
43.
EngelMGSmithJMaoK, et al.Evidence for preserved insulin responsiveness in the aging rat brain. Geroscience2022; 44: 2491–2508.
44.
WaltersROAriasEDiazA, et al.Sarcosine is uniquely modulated by aging and dietary restriction in rodents and humans. Cell Rep2018; 25: 663–676.e666.
45.
ShiQChangCSalibaA, et al.Microglial mTOR activation upregulates Trem2 and enhances β-amyloid plaque clearance in the 5XFAD Alzheimer's disease model. J Neurosci2022; 42: 5294–5313.
46.
DicksonTCVickersJC. The morphological phenotype of β-amyloid plaques and associated neuritic changes in Alzheimer’s disease. Neuroscience2001; 105: 99–107.
47.
HuangS-MMouriAKokuboH, et al.Neprilysin-sensitive synapse-associated amyloid-beta peptide oligomers impair neuronal plasticity and cognitive function. J Biol Chem2006; 281: 17941–17951.
48.
CasaliBTMacPhersonKPReed-GeaghanEG, et al.Microglia depletion rapidly and reversibly alters amyloid pathology by modification of plaque compaction and morphologies. Neurobiol Dis2020; 142: 104956.
49.
LemkeGHuangY. The dense-core plaques of Alzheimer’s disease are granulomas. J Exp Med2022; 219: e20212477.
50.
TalbotKWangH-YKaziH, 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 Invest2012; 122: 1316–1338.
51.
TramutolaATriplettJCDi DomenicoF, et al.Alteration of mTOR signaling occurs early in the progression of Alzheimer disease (AD): analysis of brain from subjects with pre-clinical AD, amnestic mild cognitive impairment and late-stage AD. J Neurochem2015; 133: 739–749.
52.
GiuffridaMLTomaselloFCaraciF, et al.Beta-amyloid monomer and insulin/IGF-1 signaling in Alzheimer's disease. Mol Neurobiol2012; 46: 605–613.
53.
CohenEPaulssonJFBlinderP, et al.Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Cell2009; 139: 1157–1169.
54.
GéraldineGCarolineGZaynaC, et al.Blocking IGF signaling in adult neurons alleviates Alzheimer's disease pathology through amyloid-β clearance. J Neurosci2015; 35: 11500.
55.
LongCHanXYangY, et al.Efficacy of intranasal insulin in improving cognition in mild cognitive impairment or dementia: a systematic review and meta-analysis. Front Aging Neurosci2022; 14: 963933.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
