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Molecular Neurobiology

, Volume 56, Issue 7, pp 4639–4652 | Cite as

Removal of p75 Neurotrophin Receptor Expression from Cholinergic Basal Forebrain Neurons Reduces Amyloid-β Plaque Deposition and Cognitive Impairment in Aged APP/PS1 Mice

  • Lei Qian
  • Michael R. Milne
  • Stephanie Shepheard
  • Mary-Louise Rogers
  • Rodrigo Medeiros
  • Elizabeth J. CoulsonEmail author
Article

Abstract

The degeneration of cholinergic basal forebrain (cBF) neurons in Alzheimer’s disease (AD) leads to the cognitive impairment associated with this condition. cBF neurons express the p75 neurotrophin receptor (p75NTR), which mediates cell death, and the extracellular domain of p75NTR can bind to amyloid beta (Aβ) and promote its degradation. Here, we investigated the contribution of cBF neuronal p75NTR to the progression of AD by removing p75NTR from cholinergic neurons in the APP/PS1 familial AD mouse strain. Conditional loss of p75NTR slowed cognitive decline and reduced both Aβ accumulation into plaques and gliosis. Expression of the amyloid protein precursor and its cleavage enzymes ADAM10 and BACE1 were unchanged. There was also no upregulation of p75NTR in non-cholinergic cell types. This indicates that a direct interaction between cBF-expressed p75NTR and Aβ does not contribute significantly to the regulation of Aβ load. Rather, loss of p75NTR from cBF neurons, which results in increased cholinergic innervation of the cortex, appears to regulate alternative, more dominant, Aβ clearance mechanisms.

Keywords

Cholinergic basal forebrain p75 neurotrophin receptor Alzheimer’s disease Cognitive impairment Amyloid plaque p75 extracellular domain Conditional knockout 

Notes

Acknowledgements

We thank other members of our laboratories, particularly Bree Rumballe (Coulson Lab) and Micell Cardoso (Rogers Lab) for administrative and technical assistance respectively, as well as helpful discussions, Luke Hammond for assistance with microscopy analysis and Rowan Tweedale for critical reading and editing of the manuscript.

Funding

This work was supported by the Australian National Health and Medical Research Council of Australia [project grant 1049236 to EJC; project grant 1139469 and Boosting Dementia Fellowship 1139469 to RM], and a Motor Neuron Disease Australia Grant in Aid [MLR,SS].

Compliance with Ethical Standards

All procedures were approved by the University of Queensland Animal Ethics Committee and conducted in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes.

Conflict of Interest

The authors declare no competing interests.

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Authors and Affiliations

  1. 1.Queensland Brain Institute, Clem Jones Centre for Ageing Dementia ResearchThe University of QueenslandBrisbaneAustralia
  2. 2.School of Biomedical SciencesThe University of QueenslandBrisbaneAustralia
  3. 3.Centre for Neuroscience, College of Medicine and Public HealthFlinders UniversityAdelaideAustralia

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