Dick Swaab met Cladio Cuello

Challenging Dogmas: Unveiling the Brain NGF Metabolic Pathway Alzheimer’s Cholinergic Atrophy.

Nerve Growth Factor regulates the daily maintenance of the phenotype of cell bodies and synapses of basal forebrain cholinergic neurons (BFCNs), a cholinergic system that plays a fundamental role in memory, learning, and attention. In Alzheimer’s disease (AD) pathology, BFCNs undergo atrophy, leading to a widespread loss of their synaptic terminal contacts in the cerebral cortex and hippocampus. The neuronal atrophy and cholinergic synaptic loss in AD were originally not attributed to a failure of NGF trophic support, as studies of AD brains have shown that 1) NGF synthesis remains intact and 2) there is a superabundance of its NGF precursor protein (ProNGF) — a longstanding dogma which has been prevailed for decades. Our lab resolved this paradox with the discovery of a “brain NGF metabolic pathway,” which regulates the activity-dependent release of proNGF, its extracellular conversion to mature NGF, and the subsequent degradation of receptor-unbound mNGF. We found that this finely controlled metabolic process is dysregulated in AD brains, leading to impaired proNGF-tomNGF conversion and increased mNGF degradation. This metabolic NGF disruption accounts for the early, progressive atrophy of NGF-dependent BFCNs in Alzheimer’s—an abnormal neurochemical process which is initiated at preclinical AD stages and holds promise for identifying additional body fluids biomarkers that signal AD pathology at its preclinical stages.