The role of nerve growth factor receptors in cholinergic basal forebrain degeneration in prodromal Alzheimer disease

Dysfunction of nerve growth factor (NGF) and its high (TrkA) and low (p75(NTR)) affinity receptors has been suggested to underlie the selective degeneration of the nucleus basalis (NB) cholinergic cortical projection neurons in end stage Alzheimer disease (AD). Whether the NGF system is dysfunctional during the prodromal stages of AD has only recently been evaluated. Surprisingly, the number of choline acetyltransferase-containing neurons remains stable despite a significant reduction in NGF receptor-positive cells in people with mild cognitive impairment (MCI), suggesting a phenotypic NGF receptor downregulation but not a frank loss of NB neurons during prodromal AD. Moreover, there is a loss of cortical TrkA in the face of stable p75(NTR) and increased proNGF levels, the precursor molecule of mature NGF, in early AD. Depending upon the cellular context these changes may result in increased pro-apoptotic signaling, cell survival, or a defect in retrograde transport mechanisms. Alterations in NGF and its receptors within the cholinotrophic NB system in early AD suggest that NGF-mediated cell signaling is required for the long-term survival of these neurons. Therapeutic neurotrophic intervention might delay or prevent NB neuron degeneration and preserve cholinergic cortical function during prodromal AD.