Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comparative Study
. 2024 Aug 1;16(1):173.
doi: 10.1186/s13195-024-01537-1.

Comparing regional brain uptake of incretin receptor agonists after intranasal delivery in CD-1 mice and the APP/PS1 mouse model of Alzheimer's disease

Noor Abdulhameed  1 , Alice Babin  1 , Kim Hansen  1 , Riley Weaver  1 , William A Banks  1   2 , Konrad Talbot  3 , Elizabeth M Rhea  4   5
Affiliations
Comparative Study

Comparing regional brain uptake of incretin receptor agonists after intranasal delivery in CD-1 mice and the APP/PS1 mouse model of Alzheimer's disease

Noor Abdulhameed et al. Alzheimers Res Ther. .

Abstract

_targeting brain insulin resistance (BIR) has become an attractive alternative to traditional therapeutic treatments for Alzheimer's disease (AD). Incretin receptor agonists (IRAs), _targeting either or both of the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, have proven to reverse BIR and improve cognition in mouse models of AD. We previously showed that many, but not all, IRAs can cross the blood-brain barrier (BBB) after intravenous (IV) delivery. Here we determined if widespread brain uptake of IRAs could be achieved by circumventing the BBB using intranasal (IN) delivery, which has the added advantage of minimizing adverse gastrointestinal effects of systemically delivered IRAs. Of the 5 radiolabeled IRAs tested (exenatide, dulaglutide, semaglutide, DA4-JC, and DA5-CH) in CD-1 mice, exenatide, dulaglutide, and DA4-JC were successfully distributed throughout the brain following IN delivery. We observed significant sex differences in uptake for DA4-JC. Dulaglutide and DA4-JC exhibited high uptake by the hippocampus and multiple neocortical areas. We further tested and found the presence of AD-associated Aβ pathology minimally affected uptake of dulaglutide and DA4-JC. Of the 5 tested IRAs, dulaglutide and DA4-JC are best capable of accessing brain regions most vulnerable in AD (neocortex and hippocampus) after IN administration. Future studies will need to be performed to determine if IN IRA delivery can reduce BIR in AD or animal models of that disorder.

Keywords: Alzheimer’s disease; GLP-1; Incretin receptor agonist; Insulin signaling; Intranasal.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Regional brain distribution of intranasally administered IRAs in CD-1 mice. Mean %Inj/g values 30 min after IN delivery represented in drawings of mid-sagittal sections. For dulaglutide in males, some regions (Olf Bulb, OC, Hy) exceeded the scale, indicated by hatch marks (see Supplemental Table 1 for %Inj/g value). The same scale bar (0-0.14%Inj/g) was used for each IRA to best compare against the other IRAs. n = 4/sex/region/IRA. Olf bulb = olfactory bulb, FC = frontal cortex, Str = striatum, Hy = hypothalamus, Thal = thalamus, PC = parietal cortex, OC = occipital cortex, Cereb = cerebellum, Mid Brain = midbrain, Pons/Med = pons/medulla
Fig. 2
Fig. 2
Comparison of whole brain uptake of radiolabeled IRAs in CD-1 mice 30 min after intranasal (IN) or intravenous (IV) delivery. The IN data (open bars) are from the present study, limited to male mice. The IV data (closed bars) are from our previous studies in male mice [65, 66]. ANOVA was statistically significant due to IRA (p = 0.0023), route of delivery (p < 0.0001), and there was an IRA by route interaction (p = 0.0192). Route post hoc differences are as marked, *p < 0.05. n = 2/IRA IV, n = 4/IRA IN
Fig. 3
Fig. 3
Maximum IRA uptake in CD-1 mice following IN delivery. Maximum averages (%Inj/g or %Inj/ml) for males (closed bars) and females (open bars) are presented for (A) whole brain, (B) olfactory bulb, (C) neocortex, (D) hippocampus, (E) hypothalamus (IRA x sex p < 0.05), and (F) serum. Within each region, there was a significant difference between IRAs (p < 0.05). ANOVA within sex: ±p < 0.05 vs. semaglutide, Ψp < 0.05 vs. dulaglutide, βp < 0.05 vs. DA4-JC, αp < 0.05 vs. DA5-CH. *p < 0.05 as marked within IRA. Exenatide n = 4 M/4F, semaglutide n = 3 M/5F, dulaglutide n = 4 M/4F, DA4-JC n = 4 F/4 M, DA5-CH n = 4 M/4F. M: male, F: female
Fig. 4
Fig. 4
Saturability of 125I/14C-IRA brain uptake following IN delivery in CD-1 mice. 125I/14C-IRA was co-administered with (lighter bar) or without (darker bar) 1 µg non-radioactive IRA and %Inj/g or %Inj/ml calculated 30 min after delivery for (A) whole brain, (B) olfactory bulb, (C) frontal cortex/striatum, (D) hippocampus, (E) hypothalamus, and (F) serum. Unpaired t-test: *p < 0.05 as marked. Exenatide n = 3 M/2F per group, semaglutide n = 3 M/2F per group, dulaglutide n = 6 M per group, DA4-JC n = 3 M/4F per group, DA5-CH n = 4 M/5F per group. M: male, F: female
Fig. 5
Fig. 5
Dulaglutide distribution in APP/PS1 male mice and WT littermate males following IN delivery. Distribution in (A) whole brain, (B) olfactory bulb, (C) neocortex (frontal + parietal + occipital), (D) hippocampus, (E) hypothalamus, and (F) serum. ANOVA time *p < 0.05 for all regions; post hoc: bp<0.05 vs. 5 min only in WT; there was no effect due to the AD transgene. See Supp Table 2 for additional statistical differences. n = 3–4/time point/genotype
Fig. 6
Fig. 6
Dulaglutide distribution in APP/PS1 female mice and WT littermate females following IN delivery. Distribution in (A) whole brain, (B) olfactory bulb, (C) neocortex (frontal + parietal + occipital), (D) hippocampus, (E) hypothalamus, and (F) serum. The ANOVA does not include the 15 min time point. ANOVA time *p < 0.05 for all regions; post hoc: bp<0.05 vs. 5 min, WT or APP/PS1 as indicated. ANOVA genotype and time by genotype in hippocampus p < 0.05; post hoc: #p < 0.05 as marked. See Supp Table 2 for additional statistical differences. n = 3–4/time point/genotype, except n = 0 for 15 min APP/PS1
Fig. 7
Fig. 7
DA4-JC distribution in APP/PS1 male mice and WT littermate males following IN delivery. Distribution in (A) whole brain, (B) olfactory bulb, (C) neocortex (frontal + parietal + occipital), (D) hippocampus, (E) hypothalamus, and (F) serum. ANOVA time *p < 0.05 for serum; there was no effect due to the AD transgene. See Supp Table 3 for additional statistical differences. n = 2–4/time point/genotype
Fig. 8
Fig. 8
DA4-JC distribution in APP/PS1 female mice and WT littermate females following IN delivery. Distribution in (A) whole brain, (B) olfactory bulb, (C) neocortex (frontal + parietal + occipital), (D) hippocampus, (E) hypothalamus, and (F) serum. ANOVA time *p < 0.05 for hypothalamus; ANOVA genotype *p < 0.05 for whole brain (neocortex p = 0.096, serum p = 0.064); post hoc: #p < 0.05 as marked. See Supp Table 3 for additional statistical differences. n = 1–4/time point/genotype
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. 2023 Alzheimer’s disease facts and figures. Alzheimer’s & dementia: the journal of the Alzheimer’s Association. 2023;19(4):1598 – 695. - PubMed
    1. Jellinger KA. Neuropathological assessment of the Alzheimer spectrum. J Neural Transm (Vienna). 2020;127(9):1229–56. 10.1007/s00702-020-02232-9 - DOI - PubMed
    1. Tao Q, Ang TFA, DeCarli C, Auerbach SH, Devine S, Stein TD, et al. Association of Chronic Low-grade inflammation with risk of Alzheimer Disease in ApoE4 carriers. JAMA Netw Open. 2018;1(6):e183597. 10.1001/jamanetworkopen.2018.3597 - DOI - PMC - PubMed
    1. Sosa-Ortiz AL, Acosta-Castillo I, Prince MJ. Epidemiology of dementias and Alzheimer’s disease. Arch Med Res. 2012;43(8):600–8. 10.1016/j.arcmed.2012.11.003 - DOI - PubMed
    1. Sims JR, Zimmer JA, Evans CD, Lu M, Ardayfio P, Sparks J, et al. Donanemab in early symptomatic Alzheimer Disease: the TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023;330(6):512–27. 10.1001/jama.2023.13239 - DOI - PMC - PubMed

Publication types

MeSH terms

LinkOut - more resources

  NODES
admin 7
Association 2
twitter 2