Title:The NGF Metabolic Pathway in the CNS and its Dysregulation in Down Syndrome and Alzheimer’s Disease
Volume: 13
Issue: 1
Author(s): M. Florencia Iulita and A. Claudio Cuello
Affiliation:
关键词:
Alzheimer's disease
摘要: It is well established that individuals with Down syndrome develop Alzheimer’s disease
neuropathology by middle age. Both in Alzheimer’s disease and Down syndrome, this is accompanied
by the atrophy of NGF-dependent cholinergic neurons of the basal forebrain. An NGF trophic compromise
in Alzheimer’s disease had been early suspected. This hypothesis was discarded with the
finding of unaltered NGF mRNA synthesis and of increased NGF precursor levels (proNGF) in postmortem
Alzheimer’s disease brains. The possibility of an NGF trophic disconnection has been recently
revisited at the light of a newly discovered extracellular NGF metabolic pathway; where proNGF is released in an
activity-dependent manner and converted by plasmin to mature NGF in the extracellular space. Mature NGF is ultimately
degraded by the metalloprotease MMP-9. This pathway has been shown to be compromised in Alzheimer’s disease and
Down syndrome brains, thus reviving the trophic factor hypothesis to explain the atrophy of basal forebrain cholinergic
neurons in these disorders. This chapter will discuss the physiological role of NGF and its biological significance to cholinergic
neurons of the CNS, and present the evidence for a dysregulation of the NGF metabolism in Alzheimer’s disease
and Down syndrome.
