Removal of p75 neurotrophin receptor expression from cholinergic basal forebrain neurons reduces amyloid-β plaque deposition and cognitive impairment in aged APP/PS1 mice

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