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

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 (p75^NTR), which mediates cell death, and the extracellular domain of p75^NTR can bind to amyloid beta (Aβ) and promote its degradation. Here, we investigated the contribution of cBF neuronal p75^NTR to the progression of AD by removing p75^NTR from cholinergic neurons in the APP/PS1 familial AD mouse strain. Conditional loss of p75^NTR 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 p75^NTR in non-cholinergic cell types. This indicates that a direct interaction between cBF-expressed p75^NTR and Aβ does not contribute significantly to the regulation of Aβ load. Rather, loss of p75^NTR 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.