Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease

Abstract

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, b-secretase, and active form of c-secretase) are up-regulated, leading to an increased production of amyloid b peptide (Ab) and to its intracellular aggregation in molecular species of different sizes. Contextually, the Ab released pool generates an autocrine toxic loop in the same healthy neurons. At the same time tau protein undergoes anomalous, GSKb-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 b and c secretase inhibitors or anti-Ab antibodies and appear to be causally correlated to TrkA, p75CTF, Ab, and PS1 molecular association in an Ab-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. '

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

“…Reduced BDNF levels 39,40 Increasing BDNF & NGF levels is beneficial in disease models [51][52][53][54] Increased p75 NTR levels and signalling 75,172 Decreased Trk receptor levels and signalling 75,172 Increased Gsk3ß activity 66,173 Altered ERK activity 174 Reduced velocity and efficiency of axonal transport of BDNF 65,66 Apoptotic pathways Increased caspase-6 activity 89,90 Caspase-6 cleavage of disease proteins [89][90][91][92] Preventing caspase cleavage of disease proteins is beneficial in mouse models 93,94 Posttranslational modifications Palmitoylation of disease proteins is linked to aggregate formation 118,119 Phosphorylation of disease proteins reduces their cleavage by caspases 105,106 HDAC inhibition is beneficial in disease models 69,126,127 Protein aggregation and clearance mechanisms Misfolding and aggregation of disease proteins 128 UPS impairment 144,145 Impaired autophagy 161 Upregulation of autophagy is beneficial in disease models 153,155,156,158,162,163,165,167,<...>…”

Amyloid Beta monomers regulate cyclic adenosine monophosphate response element binding protein functions by activating type‐1 insulin‐like growth factor receptors in neuronal cells

“…Specifically, soluble Aβ oligomers are fundamental to promote neurotoxicity (Klein, 2001; Walsh & Selkoe, 2007) through different ways (Ferreira & Klein, 2011; Pearson‐Leary & McNay, 2012), including altered levels of neurotrophic factors (NTFs) (Calissano et al ., 2010; Budni et al ., 2015). Among these, brain‐derived neurotrophic factor (BDNF) (Barde et al ., 1982) is essential in sustaining physiological processes of the normal adult brain (Nagahara & Tuszynski, 2011), by tuning: (i) dendritic branching and spine morphology (Horch & Katz, 2002) and (ii) synaptic plasticity and long‐term potentiation (Figurov et al ., 1996) and therefore learning and memory.…”

Neurotrophic and antioxidant potential of neuropeptides and trace elements

“…Основной функцией NGF в здоровом взрослом мозге считается обеспечение выживания и нормального функци-онирования холинергических нейронов базальных ганглиев переднего мозга, регулирующих в свою очередь активность гиппокама и неокортекса [4,5].…”