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Mol Neurobiol. 2018 Oct 29. doi: 10.1007/s12035-018-1404-2. [Epub ahead of print]

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

Author information

1
Queensland Brain Institute, Clem Jones Centre for Ageing Dementia Research, The University of Queensland, Brisbane, QLD, 4072, Australia.
2
School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia.
3
Centre for Neuroscience, College of Medicine and Public Health, Flinders University, Adelaide, SA, 5001, Australia.
4
Queensland Brain Institute, Clem Jones Centre for Ageing Dementia Research, The University of Queensland, Brisbane, QLD, 4072, Australia. e.coulson@uq.edu.au.
5
School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia. e.coulson@uq.edu.au.

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:

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

PMID:
30374941
DOI:
10.1007/s12035-018-1404-2

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