Differences in the cellular uptake and intracellular itineraries of amyloid beta proteins 40 and 42

Ramifications for the Alzheimer's drug discovery

Rajesh S. Omtri, Michael W. Davidson, Balasubramaniam Arumugam, Joseph F. Poduslo, Karunya K. Kandimalla

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Mounting evidence suggests that the pathological hallmarks of Alzheimer's disease (AD), neurofibrillary tangles and parenchymal amyloid plaques, are downstream reflections of neurodegeneration caused by the intraneuronal accumulation of amyloid-β proteins (Aβ), particularly Aβ42 and Aβ40. While the neurotoxicity of more amyloidogenic but less abundant Aβ42 is well documented, the effect of Aβ40 on neurons has been understudied. The Aβ40 expression in the presymptomatic AD brain is ten times greater than that of Aβ42. However, the Aβ40:42 ratio decreases with AD progression and coincides with increased amyloid plaque deposition in the brain. Hence, it is thought that Aβ40 protects neurons from the deleterious effects of Aβ42. The pathophysiological pathways involved in the neuronal uptake of Aβ40 or Aβ42 have not been clearly elucidated. Lack of such critical information obscures therapeutic targets and thwarts rational drug development strategies aimed at preventing neurodegeneration in AD. The current study has shown that fluorescein labeled Aβ42 (F-Aβ42) is internalized by neurons via dynamin dependent endocytosis and is sensitive to membrane cholesterol, whereas the neuronal uptake of F-Aβ40 is energy independent and nonendocytotic. Following their uptake, both F-Aβ40 and F-Aβ42 did not accumulate in early/recycling endosomes; F-Aβ42 but not F-Aβ40 accumulated in late endosomes and in the vesicles harboring caveolin-1. Furthermore, F-Aβ42 demonstrated robust accumulation in the lysosomes and damaged their integrity, whereas F-Aβ40 showed only a sparse lysosomal accumulation. Such regulated trafficking along distinct pathways suggests that Aβ40 and Aβ42 exercise differential effects on neurons. These differences must be carefully considered in the design of a pharmacological agent intended to block the neurodegeneration triggered by Aβ proteins.

Original languageEnglish (US)
Pages (from-to)1887-1897
Number of pages11
JournalMolecular Pharmaceutics
Volume9
Issue number7
DOIs
StatePublished - Jul 2 2012

Fingerprint

Drug Discovery
Fluorescein
Alzheimer Disease
Neurons
Endosomes
Amyloid Plaques
Dynamins
Caveolin 1
Serum Amyloid A Protein
Asymptomatic Diseases
Neurofibrillary Tangles
Brain
Endocytosis
Lysosomes
Disease Progression
Cholesterol
Pharmacology
Membranes
amyloid beta-protein (40-42)
Pharmaceutical Preparations

Keywords

  • Alzheimer's disease
  • cellular trafficking
  • cholesterol
  • endocytosis
  • lysosomes
  • neurodegeneration

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Molecular Medicine
  • Drug Discovery

Cite this

Differences in the cellular uptake and intracellular itineraries of amyloid beta proteins 40 and 42 : Ramifications for the Alzheimer's drug discovery. / Omtri, Rajesh S.; Davidson, Michael W.; Arumugam, Balasubramaniam; Poduslo, Joseph F.; Kandimalla, Karunya K.

In: Molecular Pharmaceutics, Vol. 9, No. 7, 02.07.2012, p. 1887-1897.

Research output: Contribution to journalArticle

Omtri, Rajesh S. ; Davidson, Michael W. ; Arumugam, Balasubramaniam ; Poduslo, Joseph F. ; Kandimalla, Karunya K. / Differences in the cellular uptake and intracellular itineraries of amyloid beta proteins 40 and 42 : Ramifications for the Alzheimer's drug discovery. In: Molecular Pharmaceutics. 2012 ; Vol. 9, No. 7. pp. 1887-1897.
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