Correction of microtubule defects within Aβ plaque-associated dystrophic axons results in lowered Aβ release and plaque deposition.

Abstract

The hallmark pathologies of the Alzheimer's disease (AD) brain are amyloid beta (Aβ)-containing senile plaques and neurofibrillary tangles formed from the microtubule (MT)-binding tau protein. Tau becomes hyperphosphorylated and disengages from MTs in AD, with evidence of resulting MT structure/function defects. Brain-penetrant MT-stabilizing compounds can normalize MTs and axonal transport in mouse models with tau pathology, thereby reducing neuron loss and decreasing tau pathology. MT dysfunction is also observed in dystrophic axons adjacent to Aβ plaques, resulting in accumulation of amyloid precursor protein (APP) and BACE1 with the potential for enhanced localized Aβ generation. We have examined whether the brain-penetrant MT-stabilizing compound CNDR-51657 might decrease plaque-associated axonal dystrophy and Aβ release in 5XFAD mice that develop an abundance of Aβ plaques. Administration of CNDR-51657 to 1.5-month-old male and female 5XFAD mice for 4 or 7 weeks led to decreased soluble brain Aβ that coincided with reduced APP and BACE1 levels, resulting in decreased formation of insoluble Aβ deposits. These data suggest a vicious cycle whereby initial Aβ plaque formation causes MT disruption in nearby axons, resulting in the local accumulation of APP and BACE1 that facilitates additional Aβ generation and plaque deposition. The ability of a MT-stabilizing compound to attenuate this cycle, and also reduce deficits resulting from reduced tau binding to MTs, suggests that molecules of this type hold promise as potential AD therapeutics.

• Authors: Yuemang Yao, Goodwell Nzou, Thibault Alle, Wangchen Tsering, Shaniya Maimaiti, John Q Trojanowski, Virginia M-Y Lee, Carlo Ballatore, Kurt R Brunden
• Journal: Alzheimer's & dementia : the journal of the Alzheimer's Association (Alzheimers Dement) Vol. 16 Issue 10 Pg. 1345-1357 (10 2020) ISSN: 1552-5279 [Electronic] United States
• PMID: 32918367 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2020 the Alzheimer's Association.

Chemical References

• Amyloid beta-Peptides
• Hydrocarbons, Halogenated
• Triazoles
• cevipabulin

Topics

• Amyloid beta-Peptides (metabolism)
• Animals
• Axons (pathology)
• Brain (drug effects, metabolism, pathology)
• Disease Models, Animal
• Female
• Humans
• Hydrocarbons, Halogenated (pharmacology)
• Male
• Mice
• Mice, Transgenic
• Microtubules (drug effects, pathology)
• Plaque, Amyloid (pathology)
• Triazoles (pharmacology)