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

Andrew L. Zhou, Nidhi Sharda, Vidur V Sarma, Kristen M. Ahlschwede, Geoffry L. Curran, Xiaojia Tang, Joseph F. Poduslo, Krishna R. Kalari, Val J. Lowe, Karunya K. Kandimalla

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1031-1044
Number of pages14
JournalJournal of Alzheimer's Disease
Volume85
Issue number3
DOIs
StatePublished - 2022

Bibliographical note

Funding Information:
This work was supported by the Minnesota Partnership for Biotechnology and Medical Genomics [Grant 00056030], the Dr. Paul B. Myrdal Memorial Pre-Doctoral Fellowship in Pharmaceutics, the Ronald J. Sawchuk Fellowship in Pharmacokinetics, and the Theodore H. Rowell Graduate Fellowship.

Publisher Copyright:
© 2022 - IOS Press. All rights reserved.

Keywords

  • Aging
  • amyloid-β
  • blood-brain barrier
  • insulin
  • pharmacokinetics

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

Fingerprint

Dive into the research topics of 'Age-Dependent Changes in the Plasma and Brain Pharmacokinetics of Amyloid-β Peptides and Insulin'. Together they form a unique fingerprint.

Cite this