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Abstract
Age-related degeneration of basal forebrain cholinergic neurons (BFCNs) is linked to cognitive impairment. The p75 neurotrophin receptor (p75NTR) has been proposed to mediate neuronal degeneration in aging. Therefore, we tested the hypothesis that modifying p75NTR function would prevent or reverse aging-related neuronal degeneration using LM11A-31, a small molecule p75NTR 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 p75NTR activity can prevent and potentially reverse age-associated BFCN degeneration. Moreover, this may be achieved therapeutically with orally bioavailable agents such as LM11A-31.
Highlights
Basal forebrain cholinergic neurons (BFCNs) provide cholinergic input to broad regions of the cortex and hippocampus in rodents, humans and other mammals[1,2] which promotes synaptic plasticity and supports mechanisms serving attention, working memory and processing speed[3,4,5,6]
The present study demonstrates an age-associated decrease in basal forebrain cholinergic neurons (BFCNs) area and loss of neurite length with no significant changes detected in BFCN number
Several lines of evidence have suggested that p75 neurotrophin receptor (p75NTR) related mechanisms contribute to age-associated BFCN degeneration
Summary
Basal forebrain cholinergic neurons (BFCNs) provide cholinergic input to broad regions of the cortex and hippocampus in rodents, humans and other mammals[1,2] which promotes synaptic plasticity and supports mechanisms serving attention, working memory and processing speed[3,4,5,6]. P75NTR in its unliganded state supports degenerative signaling suggesting a baseline anti-trophic effect This is supported by studies in which transgenic mice lacking intact wild-type p75NTR, demonstrate increased size of BFCNs along with enhanced cholinergic innervation of the hippocampus, cortex and amygdala[29,40,41,42,43,44]. Delivery of mature NGF to the CNS of aged rats[46,47,48,49,50,51,52,53,54,55] and non-human primates[56,57,58,59,60,61] results in reversal of age-related BFCN atrophy In these studies of mature NGF, which functions through binding to both the TrkA and p75 receptors, the contributions of each receptor and their potential interactions were not evaluated. We applied LM11A-31 to test the hypothesis that small molecule modulation of p75NTR might slow or reverse BFCN neurodegeneration associated with natural aging
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