Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease.
Converging lines of evidence on the possible connection between NGF signaling and Alzheimer's diseases (AD) are unraveling new facets which could depict this neurotrophin (NTF) in a more central role. AD animal models have provided evidence that a shortage of NGF supply may induce an AD-like syndrome. In vitro experiments, moreover, are delineating a possible temporal and causal link between APP amiloydogenic processing and altered post-translational tau modifications. After NGF signaling interruption, the pivotal upstream players of the amyloid cascade (APP, beta-secretase, and active form of gamma-secretase) are up-regulated, leading to an increased production of amyloid beta peptide (Abeta) and to its intracellular aggregation in molecular species of different sizes. Contextually, the Abeta released pool generates an autocrine toxic loop in the same healthy neurons. At the same time tau protein undergoes anomalous, GSKbeta-mediated, phosphorylation at specific pathogenetic sites (Ser262 and Thr 231), caspase(s) and calpain- I- mediated truncation, detachment from microtubules with consequent cytoskeleton collapse and axonal transport impairment. All these events are inhibited when the amyloidogenic processing is reduced by beta and gamma secretase inhibitors or anti-Abeta antibodies and appear to be causally correlated to TrkA, p75CTF, Abeta, and PS1 molecular association in an Abeta-mediated fashion. In this scenario, the so-called trophic action exerted by NGF (and possibly also by other neurotrophins) in these targets neurons is actually the result of an anti-amyloidogenic activity.
Calissano
P
P
Institute of Neurobiology and Molecular Medicine, C.N.R. Fondazione Santa Lucia, Italy. calissano@inmm.cnr.it
Matrone
C
C
Amadoro
G
G
D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D006801:Humans; D008959:Models, Neurological; D020932:Nerve Growth Factor / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000378:metabolism*
D009414:Nerve Growth Factors; D020932:Nerve Growth Factor