Journal
MOLECULAR NEUROBIOLOGY
Volume 56, Issue 7, Pages 4639-4652Publisher
SPRINGER
DOI: 10.1007/s12035-018-1404-2
Keywords
Cholinergic basal forebrain; p75 neurotrophin receptor; Alzheimer's disease; Cognitive impairment; Amyloid plaque; p75 extracellular domain; Conditional knockout
Categories
Funding
- Australian National Health and Medical Research Council of Australia [1049236, 1139469]
- Motor Neuron Disease Australia
- National Health and Medical Research Council of Australia [1139469] Funding Source: NHMRC
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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 (A beta) 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 A beta 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 A beta does not contribute significantly to the regulation of A beta load. Rather, loss of p75NTR from cBF neurons, which results in increased cholinergic innervation of the cortex, appears to regulate alternative, more dominant, A beta clearance mechanisms.
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