β-Amyloid Plaques in a Model for Sporadic Alzheimer's Disease Based on Transgenic Anti-Nerve Growth Factor Antibodies

Capsoni, Simona; Giannotta, Sabina; Cattaneo, Antonino

doi:10.1006/mcne.2002.1163

Cited by 88 publications

(59 citation statements)

References 52 publications

(65 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Gene therapy trials using NGF-grafted autologous fibroblasts injected into the basal nucleus of Meynert (23) or drugs that maintain a homeostatic balance between TrkA and p75 (24) further validate the hypothesis of an involvement of neurotrophins in AD (25) and are promising in terms of AD therapy. The NGF receptor system is also affected in AD.…”

Section: Discussionmentioning

confidence: 87%

Tyrosine kinase nerve growth factor receptor switches from prosurvival to proapoptotic activity via Abeta-mediated phosphorylation

Matrone

Marolda

Ciafrè

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The present study shows that increased Abeta production in hippocampal neurons, due to a failure of NGF signal, induces an unexpected phosphorylation of tyrosine kinase receptor A (TrkA), followed by activation of the phospholipase C ␥ (PLC␥) pathway and neuronal death. Such phosphorylation seems causally connected with 2 kinases known be involved in amyloidogenesis, Src and CDK5, and associated with ␣ and ␥ secretase-mediated p75 processing. Pharmacologic inhibition of TrkA phosphorylation and partial silencing of TrkA and/or p75 receptors prevent PLC␥ activation and protect neurons from death. Concomitantly with these events, TrkA, p75, Abeta peptides, and PS1 protein coimmunoprecipitate, suggesting their direct interplay in the subsequent onset of apoptotic death. Together, these findings depict a cellular mechanism whereby the same cellular transducing system may invert its intracellular message from trophic and antiapoptotic to a death signaling, which could also have relevance in the onset of Alzheimer's disease.N GF mediates survival, differentiation, growth, and apoptosis of neurons by binding to 2 types of cell-surface receptors. Whereas tyrosine kinase receptor A (TrkA) has been shown to transduce specific prosurvival signals via an intricate network of intracellular pathways (1), the pan-p75 receptor (p75) modulates NGF affinity for TrkA and has been shown to be involved in transducing or directly carrying out death signals (2).Recently several articles have summarized evidence for a causal link between deficit in NGF signaling, transport, and processing and the onset of Alzheimer's disease (AD) (3,4).We have recently demonstrated that the interruption of NGF signaling in neurons activates the amyloidogenic pathway and induces death through a still-unclear mechanism (5, 6).Here we show that 24 h after NGF deprivation, TrkA undergoes an unexpected NGF-independent phosphorylation. This posttranslational modification is induced either by the overproduced pool of Abeta or by exogenously added Abeta and is strictly connected to neuronal death. Such TrkA phosphorylation is largely prevented by inhibitors of CDK5 and Src intracellular pathways, both involved in amyloid processing (7-9), and by TrkA and p75 silencing.Concomitantly with TrkA phosphorylation, the amounts of p75 C-terminal fragments, which are the products of ␣ and ␥ secretase cleavage on p75 (10, 11), increase and associate with TrkA to form a molecular complex also including a full length of p75, Abeta peptides, and PS1 protein.

show abstract

Section: Discussionmentioning

confidence: 87%

Tyrosine kinase nerve growth factor receptor switches from prosurvival to proapoptotic activity via Abeta-mediated phosphorylation

Matrone

Marolda

Ciafrè

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Similar NGF-dependent modifications of site-specific tau phosphorylation have been found in the AD11 animal model, 54 in correlation with the temporal appearance of Ab peptide species. 59 Interestingly, these anti-NGF transgenic AD11 mice, in which the in vivo phenotypic knockout of mature NGF is achieved by the expression of recombinant neutralizing antibodies, resemble an AD-like neurodegeneration. 60,61 Furthermore, a caspase(s)-mediated truncation of N-terminal tau domain, which possibly interacts with dynactin/dynein motor complex, 62 also occurs in vitro and in vivo on NGF signaling interruption.…”

Section: Ngf-deprived Hippocampal Neurons: the Amyloid Cascade And Tamentioning

confidence: 99%

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

et al. 2010

View full text Add to dashboard Cite

“…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] .…”

Section: Ntf Deficits Cause Aβ Overloadmentioning

confidence: 83%

“…show Aβ accumulation and cognitive decline, for which the "neurotrophic deficit" hypothesis was recently refined as "neurotrophin imbalance" [63] . Interestingly, by crossing anti-NGF mice to p75NTR exonIII(−/−) mice, Capsoni reported a full rescue of anti-NGF mice with the Aβ phenotype by p75NTR signaling abrogation [69] .…”

Section: Glutamate Increasesmentioning

confidence: 99%

“…In the AD brain, p75NTR expression is increased while neurotrophin levels are decreased, resulting in activation of the neurodegenerative pathway (triggered by proNGF and Aβ) that leads to Aβ overproduction, neuronal death, and finally cognitive decline, rather than activation of the neurotrophic pathway (triggered by neurotrophins) that promotes neuronal survival and improves cognition [68] . Moreover, AD11transgenic mice with chronic NGF deprivation (that is, the transgenic anti-NGF antibodies bind to mature NGF much more strongly than to proNGF, leading to a decrease in mature NGF availability with a lower NGF/proNGF ratio)show Aβ accumulation and cognitive decline, for which the "neurotrophic deficit" hypothesis was recently refined as "neurotrophin imbalance" [63] . Interestingly, by crossing anti-NGF mice to p75NTR exonIII(−/−) mice, Capsoni reported a full rescue of anti-NGF mice with the Aβ phenotype by p75NTR signaling abrogation [69] .…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

β-Amyloid Plaques in a Model for Sporadic Alzheimer's Disease Based on Transgenic Anti-Nerve Growth Factor Antibodies

Cited by 88 publications

References 52 publications

Tyrosine kinase nerve growth factor receptor switches from prosurvival to proapoptotic activity via Abeta-mediated phosphorylation

Tyrosine kinase nerve growth factor receptor switches from prosurvival to proapoptotic activity via Abeta-mediated phosphorylation

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

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

Contact Info

Product

Resources

About