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Neuroscience. 2018 Mar 1;373:159-168. doi: 10.1016/j.neuroscience.2018.01.003. Epub 2018 Jan 11.

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

Author information

1
Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, MN, United States.
2
Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, United States.
3
Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria.
4
Department of Biological Science, National High Magnetic Field Laboratory, Florida State University, Tallahassee, FL, United States.
5
Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, MN, United States. Electronic address: kkandima@umn.edu.

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.

KEYWORDS:

Alzheimer’s disease; amyloid beta peptides; endocytosis; intraneuronal Aβ; vesicular trafficking

[Indexed for MEDLINE]

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