Shift in the Balance of TRKA and ProNGF in Prodromal Alzheimer ’s Disease

Abstract

Cholinergic basal forebrain (CBF) neurons in the nucleus basalis (NB) provide the primary source of cholinergic innervation to the cerebral cortex [1,2]. These cortical projection neurons undergo extensive degeneration in late-stage Alzheimer’s disease (AD), which correlates with clinical severity and disease duration [3–5]. CBF neurons require nerve growth factor (NGF) for their survival and biological activity [6–10]. NGF is derived from its precursor molecule, proNGF [11,12], which is the predominant form found in the central nervous system (CNS) andmay play a role in cell survival. Cellular responses to NGF are initiated by the binding and activation of its cognate receptors TrkA and p75NTR [6–13], which are produced within CBF neurons and transported in a retrograde manner to the cortex and hippocampus [13]. More than two decades have passed since it was hypothesized that degeneration of CBF neurons was due to a loss of neurotrophic support from target sites that produce NGF in AD [14–16]. These observations were based solely on studies that examined autopsy material harvested from late-stage AD patients. However, to better understand the roles of NGF, proNGF, the common neurotrophin receptor p75, and the high-affinity trkA receptor in basal cortical dysfunction and their relation to cognitive impairment, we examined postmortem brain tissue from subjects during the prodromal stages of AD derived from the Religious Orders Study (ROS), a longitudinal clinicopathological study of aging and dementia in retired Catholic clergy [17–22]. Each ROS participant underwent an annual detailed clinical evaluation, including a battery of tests for function in five cognitive domains (orientation, attention, memory, language, perception), and agreed to brain autopsy and neuropathological analysis. These individuals were categorized as having no cognitive impairment (NCI), mild cognitive impairment (MCI), or AD.Here, we describe