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

Author:

Zhou Andrew L.1,Sharda Nidhi1,Sarma Vidur V.1,Ahlschwede Kristen M.2,Curran Geoffry L.34,Tang Xiaojia5,Poduslo Joseph F.4,Kalari Krishna R.5,Lowe Val J.3,Kandimalla Karunya K.1

Affiliation:

1. Department of Pharmaceutics and Brain Barriers Research Center, University of Minnesota, College of Pharmacy, Minneapolis, MN, USA

2. Department of Pharmaceutical Sciences, Rosalind Franklin University of Medicine and Science, College of Pharmacy, North Chicago, IL, USA

3. Department of Radiology, Mayo Clinic, College of Medicine, Rochester, MN, USA

4. Department of Neurology, Mayo Clinic, College of Medicine, Rochester, MN, USA

5. Department of Health Sciences, Mayo Clinic, College of Medicine, Rochester, MN, USA

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.

Publisher

IOS Press

Subject

Psychiatry and Mental health,Geriatrics and Gerontology,Clinical Psychology,General Medicine,General Neuroscience

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