Differences in the cellular uptake and intracellular itineraries of amyloid beta proteins 40 and 42: ramifications for the Alzheimer's drug discovery.

Molecular Pharmaceutics
Rajesh S OmtriKarunya K Kandimalla

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 nonendo...Continue Reading

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Feb 24, 2015·Frontiers in Cellular Neuroscience·Ibrahim González-MarreroRafael Castro-Fuentes
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