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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

P021 treatment reduces abnormal hyperphosphorylation of tau in 3xTg-AD mice. Reprinted from Kazim et al. [99] with permission from Elsevier. a-d In the subiculum and the CA1 regions of the hippocampus, AT8 (phospho-tau: pSer202, pThr 205) load was significantly reduced by P021 treatment in 3xTg-AD mice (both 15–16 month-old/6 months treatment group and 21–22 month-old/12 months treatment group). a Representative photomicrographs illustrating AT8 immunoreactivity in the different regions of hippocampus from the 15–16 month-old/6 months treatment group are shown. b The AT8 load was calculated as the percentage of area occupied by immunoreactive label. Quantification of the immunoreactivity is shown as mean ± S.E.M. from Tg-Vh (n = 7), and Tg-P021 (n = 7). c Representative photomicrographs illustrating AT8 immunoreactivity in the different regions of hippocampus from the 21–22 month-old/12 months treatment group are shown. d The AT8 load calculated as the percentage of area occupied by immunoreactive label is shown as mean ± S.E.M. from Tg-Vh (n = 6), and Tg-P021 (n = 6). e, f Western blot analyses of tau pathology in 21–22 month old (12 months treatment) group. P021 treatment significantly reduced abnormal hyperphosphorylation of tau at sites pSer396/pSer404 (PHF-1) and pSer262/pSer356 (12E8). Pan-tau antibody, R134d did not show any significant difference between groups. Blots developed with human specific tau antibody 43D showed the protein expression only in 3xTg-AD mice. Quantification of the Western blots is shown as mean ± S.E.M. from WT-Vh (n = 5), WT-P021 (n = 5), Tg-Vh (n = 6), and Tg-P021 (n = 7). *p < 0.05, **p < 0.01, and ***p < 0.001. Scale bar = 100 μm. WT-Vh = wild-type control mice treated with vehicle diet; WT-P021 = wild-type mice treated with P021 diet; Tg-Vh = 3xTg-AD mice treated with vehicle diet; Tg-P021 = 3xTg-AD mice treated with P021 diet
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Fig5: P021 treatment reduces abnormal hyperphosphorylation of tau in 3xTg-AD mice. Reprinted from Kazim et al. [99] with permission from Elsevier. a-d In the subiculum and the CA1 regions of the hippocampus, AT8 (phospho-tau: pSer202, pThr 205) load was significantly reduced by P021 treatment in 3xTg-AD mice (both 15–16 month-old/6 months treatment group and 21–22 month-old/12 months treatment group). a Representative photomicrographs illustrating AT8 immunoreactivity in the different regions of hippocampus from the 15–16 month-old/6 months treatment group are shown. b The AT8 load was calculated as the percentage of area occupied by immunoreactive label. Quantification of the immunoreactivity is shown as mean ± S.E.M. from Tg-Vh (n = 7), and Tg-P021 (n = 7). c Representative photomicrographs illustrating AT8 immunoreactivity in the different regions of hippocampus from the 21–22 month-old/12 months treatment group are shown. d The AT8 load calculated as the percentage of area occupied by immunoreactive label is shown as mean ± S.E.M. from Tg-Vh (n = 6), and Tg-P021 (n = 6). e, f Western blot analyses of tau pathology in 21–22 month old (12 months treatment) group. P021 treatment significantly reduced abnormal hyperphosphorylation of tau at sites pSer396/pSer404 (PHF-1) and pSer262/pSer356 (12E8). Pan-tau antibody, R134d did not show any significant difference between groups. Blots developed with human specific tau antibody 43D showed the protein expression only in 3xTg-AD mice. Quantification of the Western blots is shown as mean ± S.E.M. from WT-Vh (n = 5), WT-P021 (n = 5), Tg-Vh (n = 6), and Tg-P021 (n = 7). *p < 0.05, **p < 0.01, and ***p < 0.001. Scale bar = 100 μm. WT-Vh = wild-type control mice treated with vehicle diet; WT-P021 = wild-type mice treated with P021 diet; Tg-Vh = 3xTg-AD mice treated with vehicle diet; Tg-P021 = 3xTg-AD mice treated with P021 diet

Mentions: In a recent study, we treated 3xTg-AD mice with P021 in diet (60 nmol/g feed) starting at 9–10 months of age (early-moderate stages of the AD-like neuropathology) for 12 months, and evaluated the therapeutic effect of the compound at 15–16 months of age (moderate-severe pathology) and at 21–22 months of age (severe pathology) [99]. P021 treatment significantly reduced tau pathology both at moderate and severe stages of the pathology in 3xTg-AD mice (Fig. 5), however, the effect of P021 on Aβ pathology was limited to a significant decrease in soluble Aβ levels and a trend towards reduction in Aβ plaque load in CA1 region of hippocampus, consistent with reduction in Aβ generation and not clearance (Fig. 6) [99]. P021 treatment also rescued cognitive impairment, enhanced dentate gyrus neurogenesis, and ameliorated synaptic deficit at moderate to severe stage of the pathology in 3xTg-AD mice (Fig. 7). The effect of P021 on tau and probably also on Aβ pathology was via increased BDNF expression mediated activation of TrkB-PI3K-AKT signaling pathway which leads to down-stream inhibition of GSK-3β activity by increase in its inhibitory phosphorylation at Ser9 by AKT (Fig. 8) [99, 194]. GSK3β is a major tau serine/threonine kinase which is known to phosphorylate tau at many different sites including Ser199, Ser202, Thr205, Ser396, and Ser404 [52, 53]. Reduction in GSK3β activity has also been demonstrated to ameliorate Aβ pathology via reduction in amyloidogenic processing of APP [195, 196].Fig. 5


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

Kazim SF, Iqbal K - Mol Neurodegener (2016)

P021 treatment reduces abnormal hyperphosphorylation of tau in 3xTg-AD mice. Reprinted from Kazim et al. [99] with permission from Elsevier. a-d In the subiculum and the CA1 regions of the hippocampus, AT8 (phospho-tau: pSer202, pThr 205) load was significantly reduced by P021 treatment in 3xTg-AD mice (both 15–16 month-old/6 months treatment group and 21–22 month-old/12 months treatment group). a Representative photomicrographs illustrating AT8 immunoreactivity in the different regions of hippocampus from the 15–16 month-old/6 months treatment group are shown. b The AT8 load was calculated as the percentage of area occupied by immunoreactive label. Quantification of the immunoreactivity is shown as mean ± S.E.M. from Tg-Vh (n = 7), and Tg-P021 (n = 7). c Representative photomicrographs illustrating AT8 immunoreactivity in the different regions of hippocampus from the 21–22 month-old/12 months treatment group are shown. d The AT8 load calculated as the percentage of area occupied by immunoreactive label is shown as mean ± S.E.M. from Tg-Vh (n = 6), and Tg-P021 (n = 6). e, f Western blot analyses of tau pathology in 21–22 month old (12 months treatment) group. P021 treatment significantly reduced abnormal hyperphosphorylation of tau at sites pSer396/pSer404 (PHF-1) and pSer262/pSer356 (12E8). Pan-tau antibody, R134d did not show any significant difference between groups. Blots developed with human specific tau antibody 43D showed the protein expression only in 3xTg-AD mice. Quantification of the Western blots is shown as mean ± S.E.M. from WT-Vh (n = 5), WT-P021 (n = 5), Tg-Vh (n = 6), and Tg-P021 (n = 7). *p < 0.05, **p < 0.01, and ***p < 0.001. Scale bar = 100 μm. WT-Vh = wild-type control mice treated with vehicle diet; WT-P021 = wild-type mice treated with P021 diet; Tg-Vh = 3xTg-AD mice treated with vehicle diet; Tg-P021 = 3xTg-AD mice treated with P021 diet
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Related In: Results  -  Collection

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Fig5: P021 treatment reduces abnormal hyperphosphorylation of tau in 3xTg-AD mice. Reprinted from Kazim et al. [99] with permission from Elsevier. a-d In the subiculum and the CA1 regions of the hippocampus, AT8 (phospho-tau: pSer202, pThr 205) load was significantly reduced by P021 treatment in 3xTg-AD mice (both 15–16 month-old/6 months treatment group and 21–22 month-old/12 months treatment group). a Representative photomicrographs illustrating AT8 immunoreactivity in the different regions of hippocampus from the 15–16 month-old/6 months treatment group are shown. b The AT8 load was calculated as the percentage of area occupied by immunoreactive label. Quantification of the immunoreactivity is shown as mean ± S.E.M. from Tg-Vh (n = 7), and Tg-P021 (n = 7). c Representative photomicrographs illustrating AT8 immunoreactivity in the different regions of hippocampus from the 21–22 month-old/12 months treatment group are shown. d The AT8 load calculated as the percentage of area occupied by immunoreactive label is shown as mean ± S.E.M. from Tg-Vh (n = 6), and Tg-P021 (n = 6). e, f Western blot analyses of tau pathology in 21–22 month old (12 months treatment) group. P021 treatment significantly reduced abnormal hyperphosphorylation of tau at sites pSer396/pSer404 (PHF-1) and pSer262/pSer356 (12E8). Pan-tau antibody, R134d did not show any significant difference between groups. Blots developed with human specific tau antibody 43D showed the protein expression only in 3xTg-AD mice. Quantification of the Western blots is shown as mean ± S.E.M. from WT-Vh (n = 5), WT-P021 (n = 5), Tg-Vh (n = 6), and Tg-P021 (n = 7). *p < 0.05, **p < 0.01, and ***p < 0.001. Scale bar = 100 μm. WT-Vh = wild-type control mice treated with vehicle diet; WT-P021 = wild-type mice treated with P021 diet; Tg-Vh = 3xTg-AD mice treated with vehicle diet; Tg-P021 = 3xTg-AD mice treated with P021 diet
Mentions: In a recent study, we treated 3xTg-AD mice with P021 in diet (60 nmol/g feed) starting at 9–10 months of age (early-moderate stages of the AD-like neuropathology) for 12 months, and evaluated the therapeutic effect of the compound at 15–16 months of age (moderate-severe pathology) and at 21–22 months of age (severe pathology) [99]. P021 treatment significantly reduced tau pathology both at moderate and severe stages of the pathology in 3xTg-AD mice (Fig. 5), however, the effect of P021 on Aβ pathology was limited to a significant decrease in soluble Aβ levels and a trend towards reduction in Aβ plaque load in CA1 region of hippocampus, consistent with reduction in Aβ generation and not clearance (Fig. 6) [99]. P021 treatment also rescued cognitive impairment, enhanced dentate gyrus neurogenesis, and ameliorated synaptic deficit at moderate to severe stage of the pathology in 3xTg-AD mice (Fig. 7). The effect of P021 on tau and probably also on Aβ pathology was via increased BDNF expression mediated activation of TrkB-PI3K-AKT signaling pathway which leads to down-stream inhibition of GSK-3β activity by increase in its inhibitory phosphorylation at Ser9 by AKT (Fig. 8) [99, 194]. GSK3β is a major tau serine/threonine kinase which is known to phosphorylate tau at many different sites including Ser199, Ser202, Thr205, Ser396, and Ser404 [52, 53]. Reduction in GSK3β activity has also been demonstrated to ameliorate Aβ pathology via reduction in amyloidogenic processing of APP [195, 196].Fig. 5

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