Age-Dependent Changes in the Plasma and Brain Pharmacokinetics of Amyloid-β Peptides and Insulin

Article type: Research Article

Authors: Zhou, Andrew L.^{a; 1} | Sharda, Nidhi^{a; 1} | Sarma, Vidur V.^{a; 1} | Ahlschwede, Kristen M.^b | Curran, Geoffry L.^{c; d} | Tang, Xiaojia^e | Poduslo, Joseph F.^d | Kalari, Krishna R.^e | Lowe, Val J.^c | Kandimalla, Karunya K.^{a; *}

Affiliations: [a] Department of Pharmaceutics and Brain Barriers Research Center, University of Minnesota, College of Pharmacy, Minneapolis, MN, USA | [b] Department of Pharmaceutical Sciences, Rosalind Franklin University of Medicine and Science, College of Pharmacy, North Chicago, IL, USA | [c] Department of Radiology, Mayo Clinic, College of Medicine, Rochester, MN, USA | [d] Department of Neurology, Mayo Clinic, College of Medicine, Rochester, MN, USA | [e] Department of Health Sciences, Mayo Clinic, College of Medicine, Rochester, MN, USA

Correspondence: [*] Correspondence to: Dr. Karunya K. Kandimalla, Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota College of Pharmacy, 9-149A, Weaver-Densford Hall, 308 Harvard St SE, Minneapolis, MN, 55455, USA. Tel.: +1 612 624 3715; Fax: +1 612 626 2125; E-mail: kkandima@umn.edu.

Note: [1] These authors contributed equally to this work.

Abstract: Background:Age is the most common risk factor for Alzheimer’s disease (AD), a neurodegenerative disorder characterized by the hallmarks of toxic amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles. Moreover, sub-physiological brain insulin levels have emerged as a pathological manifestation of AD. Objective:Identify age-related changes in the plasma disposition and blood-brain barrier (BBB) trafficking of Aβ peptides and insulin in mice. Methods:Upon systemic injection of 125I-Aβ40, 125I-Aβ42, or 125I-insulin, the plasma pharmacokinetics and brain influx were assessed in wild-type (WT) or AD transgenic (APP/PS1) mice at various ages. Additionally, publicly available single-cell RNA-Seq data [GSE129788] was employed to investigate pathways regulating BBB transport in WT mice at different ages. Results:The brain influx of 125I-Aβ40, estimated as the permeability-surface area product, decreased with age, accompanied by an increase in plasma AUC. In contrast, the brain influx of 125I-Aβ42 increased with age, accompanied by a decrease in plasma AUC. The age-dependent changes observed in WT mice were accelerated in APP/PS1 mice. As seen with 125I-Aβ40, the brain influx of 125I-insulin decreased with age in WT mice, accompanied by an increase in plasma AUC. This finding was further supported by dynamic single-photon emission computed tomography (SPECT/CT) imaging studies. RAGE and PI3K/AKT signaling pathways at the BBB, which are implicated in Aβ and insulin transcytosis, respectively, were upregulated with age in WT mice, indicating BBB insulin resistance. Conclusion:Aging differentially affects the plasma pharmacokinetics and brain influx of Aβ isoforms and insulin in a manner that could potentially augment AD risk.

Keywords: Aging, amyloid-β, blood-brain barrier, insulin, pharmacokinetics

DOI: 10.3233/JAD-215128

Journal: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1031-1044, 2022