McMaster University
Psychiatry & Behavioural Neurosciences
Dr. Fahnestock received her Honours B.Sc. in Biological Sciences from Stanford University and her Ph.D. in Biochemistry from University of California, Berkeley. Following postdoctoral work in Endocrinology at Baylor College of Medicine and Neurobiology at Stanford University, she moved to the Stanford Research Institute, where her team developed base-by-base DNA sequencing, the basis for today’s DNA sequencing machines. After a sabbatical in the Neurology Department at UCSF, Dr. Fahnestock moved to McMaster University in Hamilton, Canada. She is now a Full Professor in McMaster’s Psychiatry and Behavioural Neurosciences Department, an Associate member of the Biology Department, and co-founder of the Graduate Program in Neuroscience. Dr. Fahnestock is internationally recognized for her work on neurotrophic factor biosynthesis, regulation, expression and signalling, and their roles in Alzheimer’s disease and other neurological disorders. She has published over 100 peer-reviewed articles and has been funded continuously for over 35 years by NIH, CIHR and private foundations. She is a past President of the Southern Ontario Neuroscience Association, a co-Team leader for the Canadian Consortium on Neurodegeneration in Aging, and a co-organizer of the Alzheimer’s track at the annual Society for Brain Mapping and Therapeutics meeting.

Moderator of 1 Session

Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
05:15 PM - 07:15 PM
Room
ONSITE: 133-134

Presenter of 1 Presentation

OXIDATIVE STRESS TRIGGERS BASAL FOREBRAIN NEURODEGENERATION BY IMPAIRING PRONGF AXONAL TRANSPORT

Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
05:15 PM - 07:15 PM
Room
ONSITE: 133-134
Lecture Time
05:45 PM - 06:00 PM

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.

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