Nerve growth factor metabolic dysfunction in Alzheimer's disease and Down syndrome

• Alzheimer's disease (AD) and Down syndrome (DS) share degeneration of nerve growth factor (NGF)-dependent basal forebrain cholinergic neurons.
• In AD and DS, NGF synthesis is normal but proNGF is increased.
• In both conditions, proNGF maturation is impaired and matrix metalloprotease 9 activity is increased.
• These alterations compromise the availability of NGF to basal forebrain cholinergic neurons.
• Biomarkers of NGF metabolic deregulation could signal a central nervous system trophic disconnection.

Alzheimer's disease (AD) is a devastating neurodegenerative condition and the most common type of amnestic dementia in the elderly. Individuals with Down syndrome (DS) are at increased risk of developing AD in adulthood as a result of chromosome 21 trisomy and triplication of the amyloid precursor protein (APP) gene. In both conditions, the central nervous system (CNS) basal forebrain cholinergic system progressively degenerates, and such changes contribute to the manifestation of cognitive decline and dementia. Given the strong dependency of these neurons on nerve growth factor (NGF), it was hypothesized that their atrophy was caused by NGF deficits. However, in AD, the synthesis of NGF is not affected at the transcript level and there is a marked increase in its precursor, proNGF. This apparent paradox remained elusive for many years. In this review, we discuss the recent evidence supporting a CNS deficit in the extracellular metabolism of NGF, both in AD and in DS brains. We describe the nature of this trophic disconnection and its implication for the atrophy of basal forebrain cholinergic neurons. We further discuss the potential of NGF pathway markers as diagnostic indicators of a CNS trophic disconnection.