The goal of this study was to determine if the p75 NTR ligand, LM11A-31, could arrest or reverse the degeneration of cholinergic neurites in two mouse models of AD. Treatment of the mice was initiated at mid-to late stages of the AD-like disease progression characterized by adundant beta amyloid deposits, cholinergic degeneration and memory deficits. In mid-stage (6–8 months of age) male APPL/S mice, LM11A-31 administered for 3 months prevented and/or reversed atrophyof basal forebrain cholinergic neurites and cortical dystrophic neurites. A 1 month treatment of LM11A-31 in late-stage( 12-13 months of age) male APPL/S mice reversed the degeneration of cholinergic neurites in basal forebrain, ameliorated cortical dystrophic neurites, and normalized increased basal forebrain levels of p75NTR. Similar results were seen in late stage female Tg2576 mice. These findings suggest that LM11A-31 can reduce and/or reverse fundamental AD pathologies in late-stage AD mice. Thus, targeting p75NTR is a promising approach to reducing AD-related degenerative processes that have progressed beyond early stages.
Pharmacokinetic data is reported in: Knowles JK, Simmons DA, Nguyen TV, Vander Griend L, Xie Y, et al. (2013) Small molecule p75NTR ligand prevents cognitive deficits and neurite degeneration in an Alzheimer’s mouse model. Neurobiol Aging 34: 2052–2063.