Differential Effects of Alzheimer's Disease Aβ40 and 42 on Endocytosis and Intraneuronal Trafficking

Rajesh S. Omtri, Kevin J. Thompson, Xiaojia Tang, Chaitanya C. Gali, Ute Panzenboeck, Michael W. Davidson, Krishna R. Kalari, Karunya K. Kandimalla

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Anomalous neuronal accumulation of Aβ peptides was shown to affect synaptic transmission and contribute to neurodegeneration in Alzheimer's disease (AD) brain. Neuronal cells internalize amyloid beta (Aβ) peptides from the brain extracellular space even under normal physiological conditions, and these endocytotic pathways go awry during AD progression. We hypothesized that exposure to toxic Aβ species accumulating in AD brain contributes to perturbations in neuronal endocytosis. We have shown substantial down-regulation of KEGG endocytotic pathway genes in AD patient brain regions that accumulate Aβ compared to those in non-demented individuals. While both Aβ40 and Aβ42 perturbed endocytosis and intracellular trafficking in neuronal cells, Aβ40 had a greater effect than Aβ42. Moreover, Aβ40 decreased the neuronal uptake and lysosomal accumulation of Aβ42, which tends to oligomerize at low lysosomal pH. Hence, Aβ40 may reduce the prevalence of stable Aβ42 oligomers that are closely associated with neurodegeneration and are intercellularly propagated across the vulnerable brain regions to eventually nucleate as amyloid plaques. In conclusion, elevated brain Aβ levels and Aβ42:40 ratio apparent in the early stages of AD could perturb intraneuronal trafficking, augment the anomalous accumulation of amyloid peptides in AD brain, and drive AD pathogenesis.

Original languageEnglish (US)
Pages (from-to)159-168
Number of pages10
JournalNeuroscience
Volume373
DOIs
StatePublished - Mar 1 2018

Bibliographical note

Funding Information:
The authors acknowledge the financial assistance provided NIH / NCRR / RCMI Grant G12RR03020 (KKK), startup funding from the UMN College of Pharmacy (KKK), and the Austrian Science Fund grant DK-MCD W1226-B18 (CCG and UP), and the Medical University of Graz (Doctoral College of Metabolic and Cardiovascular Disease).

Keywords

  • Alzheimer's disease
  • amyloid beta peptides
  • endocytosis
  • intraneuronal Aβ
  • vesicular trafficking

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