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OXIDATIVE STRESS TRIGGERS BASAL FOREBRAIN NEURODEGENERATION BY IMPAIRING PRONGF AXONAL TRANSPORT
Abstract
Aims
Basal forebrain cholinergic neuron (BFCN) degeneration is a hallmark of aging and Alzheimer’s disease (AD). The reasons for this degeneration are unclear. BFCNs depend on retrograde axonal transport of neurotrophins like pro nerve growth factor (proNGF) for survival and function. ProNGF transport is reduced in aging and AD and coincides with loss of its receptor, tropomyosin-related kinase A (TrkA), while pan-neurotrophin receptor (p75NTR) levels remain unchanged. We sought to determine whether oxidative stress accounts for these reductions.
Methods
Embryonic rat BFCNs cultured in microfluidic chambers were incubated in antioxidant-poor medium to induce oxidative stress. Thioredoxin-1 and thioredoxin reductase or protein tyrosine phosphatase 1B (PTP1B) siRNA or antagonist TCS401 were applied exclusively to the cell bodies. Retrograde transport was assayed by adding quantum dot-labelled cleavage-resistant proNGF or proNGFs that bind only to TrkA (proNGF-KKE) or to p75NTR (proNGF-9/13) to the axon terminals.
Results
ProNGF retrograde transport depended upon TrkA but not p75NTR. Antioxidant deprivation reduced TrkA immunoreactivity and proNGF retrograde transport without affecting p75NTR levels. Oxidative stress triggered axonal degeneration in the presence of proNGF or proNGF-9/13 but not proNGF-KKE. Knockdown or inhibition of PTP1B, which regulates TrkA trafficking, reduced TrkA levels, decreased proNGF retrograde transport and lowered axonal uptake of proNGF-KKE. Treatment of antioxidant-deprived BFCNs with thioredoxin-1, which reactivates oxidized PTP1B, increased TrkA levels and rescued proNGF transport and axonal degeneration.
Conclusions
Oxidative stress reduces TrkA levels and proNGF transport through a PTP1B-dependent mechanism. Impaired proNGF retrograde transport due to oxidative PTP1B-mediated TrkA loss may contribute to BFCN degeneration in aging and AD.