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Neurotrophic factor small-molecule mimetics mediated neuroregeneration and synaptic repair: emerging therapeutic modality for Alzheimer's disease.

Kazim SF, Iqbal K - Mol Neurodegener (2016)

Bottom Line: It robustly inhibits tau abnormal hyperphosphorylation via increased BDNF mediated decrease in glycogen synthase kinase-3β (GSK-3β, major tau kinase) activity.P021 is a small molecular weight, BBB permeable compound with suitable pharmacokinetics for oral administration, and without adverse effects associated with native CNTF or BDNF molecule.P021 has shown beneficial therapeutic effect in several preclinical studies and has emerged as a highly promising compound for AD drug development.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurochemistry, and SUNY Downstate/NYSIBR Program in Developmental Neuroscience, New York State Institute for Basic Research (NYSIBR), 1050 Forest Hill Road, Staten Island, NY, 10314, USA.

ABSTRACT
Alzheimer's disease (AD) is an incurable and debilitating chronic progressive neurodegenerative disorder which is the leading cause of dementia worldwide. AD is a heterogeneous and multifactorial disorder, histopathologically characterized by the presence of amyloid β (Aβ) plaques and neurofibrillary tangles composed of Aβ peptides and abnormally hyperphosphorylated tau protein, respectively. Independent of the various etiopathogenic mechanisms, neurodegeneration is a final common outcome of AD neuropathology. Synaptic loss is a better correlate of cognitive impairment in AD than Aβ or tau pathologies. Thus a highly promising therapeutic strategy for AD is to shift the balance from neurodegeneration to neuroregeneration and synaptic repair. Neurotrophic factors, by virtue of their neurogenic and neurotrophic activities, have potential for the treatment of AD. However, the clinical therapeutic usage of recombinant neurotrophic factors is limited because of the insurmountable hurdles of unfavorable pharmacokinetic properties, poor blood-brain barrier (BBB) permeability, and severe adverse effects. Neurotrophic factor small-molecule mimetics, in this context, represent a potential strategy to overcome these short comings, and have shown promise in preclinical studies. Neurotrophic factor small-molecule mimetics have been the focus of intense research in recent years for AD drug development. Here, we review the relevant literature regarding the therapeutic beneficial effect of neurotrophic factors in AD, and then discuss the recent status of research regarding the neurotrophic factor small-molecule mimetics as therapeutic candidates for AD. Lastly, we summarize the preclinical studies with a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic, Peptide 021 (P021). P021 is a neurogenic and neurotrophic compound which enhances dentate gyrus neurogenesis and memory processes via inhibiting leukemia inhibitory factor (LIF) signaling pathway and increasing brain-derived neurotrophic factor (BDNF) expression. It robustly inhibits tau abnormal hyperphosphorylation via increased BDNF mediated decrease in glycogen synthase kinase-3β (GSK-3β, major tau kinase) activity. P021 is a small molecular weight, BBB permeable compound with suitable pharmacokinetics for oral administration, and without adverse effects associated with native CNTF or BDNF molecule. P021 has shown beneficial therapeutic effect in several preclinical studies and has emerged as a highly promising compound for AD drug development.

No MeSH data available.


Related in: MedlinePlus

Design and structures of CNTF small-molecule mimetics and their mechanism of action to enhance formation of NPCs and mature neurons. a Protein Data Base rendering of one 4-helix bundle of truncated human CNTF (Residues 2–187), generated from CNTF. Only one protein chain is shown for clarity. Residues 149GGLFEKKL156 are shown as a tube model, while the rest of the sequence are presented as ribbon [98]. The structures of P6 and P021 are also shown. From the neurogenic 11-mer, Ac-VGDGGLFEKKL-NH2 (P6), a truncated, still neurogenic pentamer, with an adamantylated glycine group (red oval), Ac-DGGLAG-NH2 (P021) was designed [191]. b P6 and P021 enhance neural progenitor cells (NPCs) formation and maturation and integration of new-born neurons by competitively inhibiting the LIF signaling and increasing BDNF expression respectively [99, 180, 181, 191, 192]
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Fig4: Design and structures of CNTF small-molecule mimetics and their mechanism of action to enhance formation of NPCs and mature neurons. a Protein Data Base rendering of one 4-helix bundle of truncated human CNTF (Residues 2–187), generated from CNTF. Only one protein chain is shown for clarity. Residues 149GGLFEKKL156 are shown as a tube model, while the rest of the sequence are presented as ribbon [98]. The structures of P6 and P021 are also shown. From the neurogenic 11-mer, Ac-VGDGGLFEKKL-NH2 (P6), a truncated, still neurogenic pentamer, with an adamantylated glycine group (red oval), Ac-DGGLAG-NH2 (P021) was designed [191]. b P6 and P021 enhance neural progenitor cells (NPCs) formation and maturation and integration of new-born neurons by competitively inhibiting the LIF signaling and increasing BDNF expression respectively [99, 180, 181, 191, 192]

Mentions: Our laboratory generated an 11-mer CNTF small-molecule peptide mimetic, Peptide 6 (P6; Ac-VGDGGLFEKKL-NH2), which corresponds to a biologically active region (amino acid residues 146–156) of human CNTF and was identified using epitope mapping and employing neutralizing antibodies (Fig. 4) [179, 180]. P6 has a plasma half-life of over 6 h as compared to ~ 3 min plasma half-life of recombinant CNTF, and is BBB permeable [180]. P6 acts by competitively inhibiting the LIF signaling, thus promoting the formation of neural precursor cells (NPCs), and by increasing BDNF mRNA levels, thus increasing the survival, maturation, and integration of new-born cells (Fig. 4) [180, 181]. Peripheral administration of P6 for 30 days via a subcutaneously implanted slow release bolus, was found to enhance dentate gyrus neurogenesis, neuronal plasticity, and spatial memory of the normal adult C57Bl/6 mice [180]. The intraperitoneal administration of P6 for six weeks in 6–7 month-old 3xTg-AD mice (at early stages of the AD pathology prior to Aβ plaques and neurofibrillary tangle-like pathology) ameliorated impairment in spatial reference memory and short-term episodic memory by enhancing dentate gyrus neurogenesis and neuronal plasticity in these mice [98]. The 3xTg-AD mice carry AD-related mutation including human PS1 M146V, human APP Swedish, and human tau P301L [182], and develop Aβ plaques and neurofibrillary tangle-like pathologies in a progressive and age-dependent manner, starting at ~9 and ~12 months respectively but show cognitive impairment as early as 3–5 months of age [182–185]. P6 treatment in 6–7 month-old 3xTg-AD mice could not exert any effect on Aβ and tau pathologies [98], seen in this age mice as intraneuronal Aβ accumulation and tau hyperphosphorylation, and not as plaques and tangles [87, 183]. Other preclinical studies employing P6 showed neurogenic and neurotrophic effects in animal models of sporadic AD [181], familial AD [186], Down syndrome [187], autism [188], and traumatic brain injury [189].Fig. 4


Neurotrophic factor small-molecule mimetics mediated neuroregeneration and synaptic repair: emerging therapeutic modality for Alzheimer's disease.

Kazim SF, Iqbal K - Mol Neurodegener (2016)

Design and structures of CNTF small-molecule mimetics and their mechanism of action to enhance formation of NPCs and mature neurons. a Protein Data Base rendering of one 4-helix bundle of truncated human CNTF (Residues 2–187), generated from CNTF. Only one protein chain is shown for clarity. Residues 149GGLFEKKL156 are shown as a tube model, while the rest of the sequence are presented as ribbon [98]. The structures of P6 and P021 are also shown. From the neurogenic 11-mer, Ac-VGDGGLFEKKL-NH2 (P6), a truncated, still neurogenic pentamer, with an adamantylated glycine group (red oval), Ac-DGGLAG-NH2 (P021) was designed [191]. b P6 and P021 enhance neural progenitor cells (NPCs) formation and maturation and integration of new-born neurons by competitively inhibiting the LIF signaling and increasing BDNF expression respectively [99, 180, 181, 191, 192]
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4940708&req=5

Fig4: Design and structures of CNTF small-molecule mimetics and their mechanism of action to enhance formation of NPCs and mature neurons. a Protein Data Base rendering of one 4-helix bundle of truncated human CNTF (Residues 2–187), generated from CNTF. Only one protein chain is shown for clarity. Residues 149GGLFEKKL156 are shown as a tube model, while the rest of the sequence are presented as ribbon [98]. The structures of P6 and P021 are also shown. From the neurogenic 11-mer, Ac-VGDGGLFEKKL-NH2 (P6), a truncated, still neurogenic pentamer, with an adamantylated glycine group (red oval), Ac-DGGLAG-NH2 (P021) was designed [191]. b P6 and P021 enhance neural progenitor cells (NPCs) formation and maturation and integration of new-born neurons by competitively inhibiting the LIF signaling and increasing BDNF expression respectively [99, 180, 181, 191, 192]
Mentions: Our laboratory generated an 11-mer CNTF small-molecule peptide mimetic, Peptide 6 (P6; Ac-VGDGGLFEKKL-NH2), which corresponds to a biologically active region (amino acid residues 146–156) of human CNTF and was identified using epitope mapping and employing neutralizing antibodies (Fig. 4) [179, 180]. P6 has a plasma half-life of over 6 h as compared to ~ 3 min plasma half-life of recombinant CNTF, and is BBB permeable [180]. P6 acts by competitively inhibiting the LIF signaling, thus promoting the formation of neural precursor cells (NPCs), and by increasing BDNF mRNA levels, thus increasing the survival, maturation, and integration of new-born cells (Fig. 4) [180, 181]. Peripheral administration of P6 for 30 days via a subcutaneously implanted slow release bolus, was found to enhance dentate gyrus neurogenesis, neuronal plasticity, and spatial memory of the normal adult C57Bl/6 mice [180]. The intraperitoneal administration of P6 for six weeks in 6–7 month-old 3xTg-AD mice (at early stages of the AD pathology prior to Aβ plaques and neurofibrillary tangle-like pathology) ameliorated impairment in spatial reference memory and short-term episodic memory by enhancing dentate gyrus neurogenesis and neuronal plasticity in these mice [98]. The 3xTg-AD mice carry AD-related mutation including human PS1 M146V, human APP Swedish, and human tau P301L [182], and develop Aβ plaques and neurofibrillary tangle-like pathologies in a progressive and age-dependent manner, starting at ~9 and ~12 months respectively but show cognitive impairment as early as 3–5 months of age [182–185]. P6 treatment in 6–7 month-old 3xTg-AD mice could not exert any effect on Aβ and tau pathologies [98], seen in this age mice as intraneuronal Aβ accumulation and tau hyperphosphorylation, and not as plaques and tangles [87, 183]. Other preclinical studies employing P6 showed neurogenic and neurotrophic effects in animal models of sporadic AD [181], familial AD [186], Down syndrome [187], autism [188], and traumatic brain injury [189].Fig. 4

Bottom Line: It robustly inhibits tau abnormal hyperphosphorylation via increased BDNF mediated decrease in glycogen synthase kinase-3β (GSK-3β, major tau kinase) activity.P021 is a small molecular weight, BBB permeable compound with suitable pharmacokinetics for oral administration, and without adverse effects associated with native CNTF or BDNF molecule.P021 has shown beneficial therapeutic effect in several preclinical studies and has emerged as a highly promising compound for AD drug development.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurochemistry, and SUNY Downstate/NYSIBR Program in Developmental Neuroscience, New York State Institute for Basic Research (NYSIBR), 1050 Forest Hill Road, Staten Island, NY, 10314, USA.

ABSTRACT
Alzheimer's disease (AD) is an incurable and debilitating chronic progressive neurodegenerative disorder which is the leading cause of dementia worldwide. AD is a heterogeneous and multifactorial disorder, histopathologically characterized by the presence of amyloid β (Aβ) plaques and neurofibrillary tangles composed of Aβ peptides and abnormally hyperphosphorylated tau protein, respectively. Independent of the various etiopathogenic mechanisms, neurodegeneration is a final common outcome of AD neuropathology. Synaptic loss is a better correlate of cognitive impairment in AD than Aβ or tau pathologies. Thus a highly promising therapeutic strategy for AD is to shift the balance from neurodegeneration to neuroregeneration and synaptic repair. Neurotrophic factors, by virtue of their neurogenic and neurotrophic activities, have potential for the treatment of AD. However, the clinical therapeutic usage of recombinant neurotrophic factors is limited because of the insurmountable hurdles of unfavorable pharmacokinetic properties, poor blood-brain barrier (BBB) permeability, and severe adverse effects. Neurotrophic factor small-molecule mimetics, in this context, represent a potential strategy to overcome these short comings, and have shown promise in preclinical studies. Neurotrophic factor small-molecule mimetics have been the focus of intense research in recent years for AD drug development. Here, we review the relevant literature regarding the therapeutic beneficial effect of neurotrophic factors in AD, and then discuss the recent status of research regarding the neurotrophic factor small-molecule mimetics as therapeutic candidates for AD. Lastly, we summarize the preclinical studies with a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic, Peptide 021 (P021). P021 is a neurogenic and neurotrophic compound which enhances dentate gyrus neurogenesis and memory processes via inhibiting leukemia inhibitory factor (LIF) signaling pathway and increasing brain-derived neurotrophic factor (BDNF) expression. It robustly inhibits tau abnormal hyperphosphorylation via increased BDNF mediated decrease in glycogen synthase kinase-3β (GSK-3β, major tau kinase) activity. P021 is a small molecular weight, BBB permeable compound with suitable pharmacokinetics for oral administration, and without adverse effects associated with native CNTF or BDNF molecule. P021 has shown beneficial therapeutic effect in several preclinical studies and has emerged as a highly promising compound for AD drug development.

No MeSH data available.


Related in: MedlinePlus