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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

Aβ plaques and NFTs as hallmarks of AD. AD is characterized by extracellular deposits of Aβ (senile) plaques and intraneuronal NFTs leading to neurodegeneration, and ultimately cognitive impairment and dementia. Aβ plaques are produced by the amyloidogenic processing of APP by β- and γ-secretase enzymes leading to the formation of Aβ peptides (36–43 amino acids) of which the Aβ40 and Aβ42 are the most common. Aβ42 is the most fibrillogenic and thus most amyloidogenic Aβ peptide. Aβ oligomers impair hippocampal LTP, and thus synaptic plasticity, and learning and memory. NFTs are intracellular aggregates of MAP-tau which is abnormally hyperphosphorylated by upregulation of activities of kinases such as GSK3β and Cdk5 or deficit in phosphatases such as PP2A
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Fig2: Aβ plaques and NFTs as hallmarks of AD. AD is characterized by extracellular deposits of Aβ (senile) plaques and intraneuronal NFTs leading to neurodegeneration, and ultimately cognitive impairment and dementia. Aβ plaques are produced by the amyloidogenic processing of APP by β- and γ-secretase enzymes leading to the formation of Aβ peptides (36–43 amino acids) of which the Aβ40 and Aβ42 are the most common. Aβ42 is the most fibrillogenic and thus most amyloidogenic Aβ peptide. Aβ oligomers impair hippocampal LTP, and thus synaptic plasticity, and learning and memory. NFTs are intracellular aggregates of MAP-tau which is abnormally hyperphosphorylated by upregulation of activities of kinases such as GSK3β and Cdk5 or deficit in phosphatases such as PP2A

Mentions: The histopathological hallmarks in both the sporadic and the familial forms of AD are similar and include amyloid β plaques and NFTs leading to neurodegeneration (Fig. 2) [6]. The immensely popular amyloid cascade hypothesis suggests a major etiological role of Aβ for the NFT pathology, neurodegeneration and cognitive dysfunction in AD [42]. Aβ plaques are produced by amyloidogenic processing of the transmembrane protein, APP, by β- and γ-secretase enzymes resulting in the formation of major toxic products, Aβ40 and Aβ42 peptides (Fig. 2) [12, 43, 44]. The oligomeric form of Aβ has also been suggested as the main neurotoxic state of the peptide [45]. Aβ oligomers are known to inhibit hippocampal long-term potentiation (LTP) [46], a major cellular mechanism underlying synaptic plasticity, and learning and memory [47]. Amyloid cascade hypothesis also derives its major support from the Down syndrome individuals; as part of the trisomy 21, these patients carry 3 copies of APP and almost all of them develop AD neuropathological characteristics by the age of 40 years [48, 49].Fig. 2


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

Kazim SF, Iqbal K - Mol Neurodegener (2016)

Aβ plaques and NFTs as hallmarks of AD. AD is characterized by extracellular deposits of Aβ (senile) plaques and intraneuronal NFTs leading to neurodegeneration, and ultimately cognitive impairment and dementia. Aβ plaques are produced by the amyloidogenic processing of APP by β- and γ-secretase enzymes leading to the formation of Aβ peptides (36–43 amino acids) of which the Aβ40 and Aβ42 are the most common. Aβ42 is the most fibrillogenic and thus most amyloidogenic Aβ peptide. Aβ oligomers impair hippocampal LTP, and thus synaptic plasticity, and learning and memory. NFTs are intracellular aggregates of MAP-tau which is abnormally hyperphosphorylated by upregulation of activities of kinases such as GSK3β and Cdk5 or deficit in phosphatases such as PP2A
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig2: Aβ plaques and NFTs as hallmarks of AD. AD is characterized by extracellular deposits of Aβ (senile) plaques and intraneuronal NFTs leading to neurodegeneration, and ultimately cognitive impairment and dementia. Aβ plaques are produced by the amyloidogenic processing of APP by β- and γ-secretase enzymes leading to the formation of Aβ peptides (36–43 amino acids) of which the Aβ40 and Aβ42 are the most common. Aβ42 is the most fibrillogenic and thus most amyloidogenic Aβ peptide. Aβ oligomers impair hippocampal LTP, and thus synaptic plasticity, and learning and memory. NFTs are intracellular aggregates of MAP-tau which is abnormally hyperphosphorylated by upregulation of activities of kinases such as GSK3β and Cdk5 or deficit in phosphatases such as PP2A
Mentions: The histopathological hallmarks in both the sporadic and the familial forms of AD are similar and include amyloid β plaques and NFTs leading to neurodegeneration (Fig. 2) [6]. The immensely popular amyloid cascade hypothesis suggests a major etiological role of Aβ for the NFT pathology, neurodegeneration and cognitive dysfunction in AD [42]. Aβ plaques are produced by amyloidogenic processing of the transmembrane protein, APP, by β- and γ-secretase enzymes resulting in the formation of major toxic products, Aβ40 and Aβ42 peptides (Fig. 2) [12, 43, 44]. The oligomeric form of Aβ has also been suggested as the main neurotoxic state of the peptide [45]. Aβ oligomers are known to inhibit hippocampal long-term potentiation (LTP) [46], a major cellular mechanism underlying synaptic plasticity, and learning and memory [47]. Amyloid cascade hypothesis also derives its major support from the Down syndrome individuals; as part of the trisomy 21, these patients carry 3 copies of APP and almost all of them develop AD neuropathological characteristics by the age of 40 years [48, 49].Fig. 2

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