Homage to Rita Levi-Montalcini. Molecular mechanisms of Alzheimer's disease: NGF modulation of APP processing

Abstract

The therapeutic focus of the scientific community in Alzheimer's disease (AD) has been moving in the last years from attempting late rescue against cholinergic degeneration and amyloid beta plaque clearance to (i) the discovery of blood or cerebrospinal fluid markers for early diagnosis, and (ii) early therapeutic intervention with modulators of amyloid precursor protein (APP) processing. It is currently accepted idea that subtle synaptic alterations determine the first neuronal dysfunctions and cognitive deterioration, progressing overtime into neuronal degeneration in the sporadic and late onset form AD (LOAD), the most diffuse one (90% of AD cases). Synaptic loss occurs long before the appearance of a frank neuronal degeneration in LOAD. The perturbation of the nerve growth factor (NGF) signaling system in brain neurodegenerative disease like AD and Down's syndrome was for long time considered to be a pathological event, subsequent to amyloid-driven disruption of NGF retrograde transport from the cortex and hippocampus to the cell bodies of basal forebrain cholinergic neurons. Nowadays, an increasing amount of data indicate that the observed dysregulation of NGF-TrkA (tyrosine kinase A) and proNGF-p75NTR signaling systems is a good candidate for being the primus movens in the neuropathology of sporadic AD. Accordingly, an amyloid-independent strong correlation of cognitive deficits with reduction of NGF and TrkA, and accumulation of proNGF has been recently observed in mild cognitive impairment and its progression to AD. This review highlights the current knowledge about NGF and early events occurring in LOAD. The involvement of muscarinic acetylcholine receptors, cholesterol, sirtuin1, insulin-like growth factor-1, and Sunday driver protein in APP processing are also discussed. The studies reported here confirm a multitasking ability of NGF in slowing down, through both distinct and overlapping mechanisms, the amyloidogenic processing of APP in neurons of the central nervous system. Adipobiology 2013; 5: 7-18.