Modulation of the p75 neurotrophin receptor suppresses age-related basal forebrain cholinergic neuron degeneration

Age-related degeneration of basal forebrain cholinergic neurons (BFCNs) is linked to cognitive impairment. The p75 neurotrophin receptor (p75^NTR) has been proposed to mediate neuronal degeneration in aging. Therefore, we tested the hypothesis that modifying p75^NTR function would prevent or reverse aging-related neuronal degeneration using LM11A-31, a small molecule p75^NTR modulator that downregulates degenerative and upregulates trophic receptor-associated signaling. Morphological analysis in mice showed loss of BFCN area detectable by 18 months of age. Oral administration of LM11A-31 from age 15 to 18 months resulted in a dose-related preservation of BFCN area and one month of treatment from 17 to 18 months also preserved cell area. To evaluate reversal of established neuronal atrophy, animals were treated from 21 to 25 months of age. Treatment was associated with an increase of cell size to a mean area larger than that observed at 18 months, accompanied by increases in mean MS/VDB neurite length, as well as increased cholinergic fiber density and synaptophysin pre-synaptic marker levels in the hippocampus. These findings support the idea that modulation of p75^NTR activity can prevent and potentially reverse age-associated BFCN degeneration. Moreover, this may be achieved therapeutically with orally bioavailable agents such as LM11A-31.