Activation of the Amyloidogenic Route by NGF Deprivation Induces Apoptotic Death in PC12 Cells

Matrone, Carmela; Luzio, A. Di; Meli, Giovanni; D’Aguanno, Simona; Severini, Cinzia; Ciotti, Maria Teresa; Cattaneo, Antonino; Calissano, Pietro

doi:10.3233/jad-2008-13109

Cited by 79 publications

(87 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found that the downregulation of amyloidogenic APP processing with selective b-and g-secretase(s) inhibitors or 4G8 antibody (Ab residues 17-24) significantly reduced the apoptotic death of NGF-deprived PC12 neurons. 45 In our opinion, these results not only provide the first clear evidence linking apoptosis and amyloidogenic APP metabolism, but also gives new insights into the causal and temporal sequence of events occurring during neuronal death induced by the lack of trophic supply.…”

Section: Amyloidogenesis and Apoptosismentioning

confidence: 97%

“…47 Conversely, among all cell-permeable and selective caspase(s) inhibitors tested in NGF-deprived PC12, only blockage of executor caspases 2, 12, 6 and 8 partially reduced death and Ab production, whereas pharmacological inhibition of effector caspase 3 did not exert a similar action. 45 Apoptosis induced by serum deprivation or by oxygen peroxide treatment under mild exposure conditions, at variance with NGF, evoked an apoptotic neuronal death that was not inhibited by b-and g-secretase inhibitors or by 4G8 antibody. Finally, the finding that the general caspase(s) inhibitor z-VAD did not significantly affect the production of Ab structure and cell death in NGF-deprived PC12, whereas it partially blocked caspase(s)-mediated tau truncation 48 and rescued neurons from apoptotic death 45 suggests a complex causal and temporal relationship between caspase(s), APP amyloidogenic processing and tau metabolism in NGF-deprived cell death.…”

Section: Amyloidogenesis and Apoptosismentioning

confidence: 99%

See 1 more Smart Citation

Does the term ‘trophic’ actually mean anti-amyloidogenic? The case of NGF

et al. 2010

View full text Add to dashboard Cite

Section: Amyloidogenesis and Apoptosismentioning

confidence: 97%

Section: Amyloidogenesis and Apoptosismentioning

confidence: 99%

Does the term ‘trophic’ actually mean anti-amyloidogenic? The case of NGF

et al. 2010

View full text Add to dashboard Cite

“…In vitro, NGF modulates the APP gene expression (Mobley et al, 1988;Lahiri et al, 1995;Cosgaya et al, 1996;Rossner et al, 1998;Villa et al, 2001;Ge et al, 2002) and its withdrawal induces an APP expression increase in PC12 cells (Araki et al, 1998;Matrone et al 2008a). In addition, NGF protein secretion is up-regulated by amyloid b administration in glial and neuronal cells (Olivieri et al, 2002;Schulte-Herbrüggen et al, 2007;Bulbarelli et al, 2009).…”

Section: Ngf Signaling and Amyloidogenesismentioning

confidence: 99%

“…Upon NGF deprivation, differentiated PC12 cells show an intra and extracellular accumulation of Ab, followed by apoptotic death. Both these events are largely or completely prevented by Ab antibodies, b and c secretase inhibitors or partial silencing of APP mRNA (Matrone et al, 2008a). The evidence that serum deprivation induces apoptotic death which is not prevented by anti Ab agents, suggests that the deficit of NGF supply may directly induce Ab-mediated apoptosis, probably through the activation of molecular mechanisms leading to an increase of APP expression and processing and/or to an unbalance of physiological secretase(s) activity.…”

Section: Ngf Signaling and Amyloidogenesismentioning

confidence: 99%

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

Calissano

Matrone

Amadoro

2010

Developmental Neurobiology

View full text Add to dashboard Cite

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. '

show abstract

“…This is supported by the finding that the AD11 mouse model, which expresses the recombinant monoclonal antibody αD11 that specifically neutralizes NGF thus causing NGF deprivation, shows ADlike pathology including Aβ accumulation and hippocampusdependent memory deficits [63,64] . Based on the report that activation of the amyloidogenic route by NGF deprivation induces apoptotic death in PC12 cells [65] , Matrone and colleagues further found that APP and presenilin 1 N-terminus (which is the active component endowed with γ-secretase activity) levels were increased in hippocampal neurons that were previously exposed to NGF or BDNF for 48 h followed by deprivation by anti-NGF (or -BDNF) antibodies [66] . These findings suggest that Aβ and NTF deficits cause a feedforward loop that accelerates the toxicity of Aβ sufficient to cause neuronal death.…”

mentioning

confidence: 99%

Combination of Aβ clearance and neurotrophic factors as a potential treatment for Alzheimer’s disease

et al. 2012

View full text Add to dashboard Cite

There is no effective drug to treat Alzheimer's disease (AD), a neurodegenerative disease affecting an estimated 30 million people around the world. Strongly supported by preclinical and clinical studies, amyloid-beta (Aβ) may be a target for developing drugs against AD. Meanwhile, the fact that localized neuronal death/loss and synaptic impairment occur in AD should also be considered. Neuronal regeneration, which does not occur normally in the mammalian central nervous system, can be promoted by neurotrophic factors (NTFs). Evidence from clinical trials has shown that both Aβ clearance and NTFs are potentially effective in treating AD, thus a new approach combining Aβ clearance and administration of NTFs may be an effective therapeutic strategy.Keywords: Alzheimer's disease; amyloid-beta; neurotrophic factors; treatment IntroductionAlzheimer's disease (AD) is an age-related, progressive and irreversible neurodegenerative disease that causes serious cognitive dysfunction. Its pathological hallmarks are extracellular deposits of amyloid-beta (Aβ) and intracellular neurofibrillary tangles, together with drastic synaptic and neuronal reduction or loss [1] . It has been estimated that AD affects 30 million people around the world [2] , and the past two decades have witnessed an explosion in research into the underlying mechanisms as well as potential therapeutic strategies. Although it was first described by German psychiatrist Alois Alzheimer in 1906, there is still no cure for AD, partly because the cellular and molecular mechanisms underlying it are far from clear. The Food and Drug Administration in the United Stateshas approved a limited range of drugs to treat AD, including acetylcholinesterase inhibitors (AChEIs) and N-methyl-Daspartate receptor (NMDAR) antagonists [3] , although their effects are merely symptomatic and memory-improvement occurs within a limited period. Donepezil, galantamine, rivastigmine and tacrine are AChEIs that prevent the breakdown of acetylcholine released from presynaptic terminals, increasing the residence time of the neurotransmitter within the synapse and thereby prolonging the duration of its interaction with postsynaptic receptors [4] . Memantine, an NMDAR antagonist, has been approved for the treatment of moderate and severe AD; it works by preventing the excitatory neurotoxicity induced by excessive glutamate [5] .Currently, no available pharmacological agents cure or reverse the progression of this devastating neurological disorder. It is therefore urgent to improve our understanding of its pathogenesis, and then develop an effective treatment strategy. This review aimed to provide insights Neurosci Bull February 1, 2013, 29(1): 111-120 112 into the design of potentially effective pharmaceutical treatments for AD by targeting two seemingly separate but tightly connected components, Aβ and neurotrophic factors (NTFs). Aβ as a Promising Target for AD TreatmentAβ is a peptide of 36-43 amino-acids produced from amyloid precursor protein (APP) through aberrant cleavage by...

show abstract

Activation of the Amyloidogenic Route by NGF Deprivation Induces Apoptotic Death in PC12 Cells

Cited by 79 publications

References 28 publications

Does the term ‘trophic’ actually mean anti-amyloidogenic? The case of NGF

Does the term ‘trophic’ actually mean anti-amyloidogenic? The case of NGF

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

Combination of Aβ clearance and neurotrophic factors as a potential treatment for Alzheimer’s disease

Contact Info

Product

Resources

About