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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

Multifactorial nature of AD and involvement of several different etiopathogenic mechanisms. Early-onset familial AD caused by mutations in APP, PS1, or PS2 constitutes < 1 % of AD cases. The exact causes of late-onset sporadic AD which accounts for the remaining > 99 % of AD cases are as yet largely unknown. However, aging alongside gene-environment interaction is speculated to contribute to this form of AD. Both forms of AD lead to amyloid plaque and neurofibrillary pathologies, synaptic dysfunction and neurodegeneration, and ultimately cognitive impairment
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Fig1: Multifactorial nature of AD and involvement of several different etiopathogenic mechanisms. Early-onset familial AD caused by mutations in APP, PS1, or PS2 constitutes < 1 % of AD cases. The exact causes of late-onset sporadic AD which accounts for the remaining > 99 % of AD cases are as yet largely unknown. However, aging alongside gene-environment interaction is speculated to contribute to this form of AD. Both forms of AD lead to amyloid plaque and neurofibrillary pathologies, synaptic dysfunction and neurodegeneration, and ultimately cognitive impairment

Mentions: AD, first described by German psychiatrist Alois Alzheimer in 1907 [37], is a multifactorial and heterogeneous disease, and apparently involves several different etiopathogenic mechanisms (Fig. 1) [6, 38]. The early-onset familial form of AD which is caused by mutations in amyloid β precursor protein (APP), presenilin 1 (PS1), or presenilin 2 (PS2), accounts for <1 % of all cases (Fig. 1) (for review, [39, 40]). The exact causes of the late-onset sporadic form of AD, which accounts for over 99 % of the cases, are not yet understood. The sporadic form of AD probably involves several different etiopathogenic mechanisms in concert with aging such as metabolic derangements, head trauma, metal ion toxicity, hypertension, vascular injury, smoking, psychological stress, and vitamin deficiencies (Fig. 1) [38]. No known mutations are involved in sporadic form of AD, however, the presence of one or two apolipoprotein E epsilon 4 (APOE ε4) alleles increases the disease risk ~3.5-fold or ~10-fold, respectively [39–41].Fig. 1


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

Kazim SF, Iqbal K - Mol Neurodegener (2016)

Multifactorial nature of AD and involvement of several different etiopathogenic mechanisms. Early-onset familial AD caused by mutations in APP, PS1, or PS2 constitutes < 1 % of AD cases. The exact causes of late-onset sporadic AD which accounts for the remaining > 99 % of AD cases are as yet largely unknown. However, aging alongside gene-environment interaction is speculated to contribute to this form of AD. Both forms of AD lead to amyloid plaque and neurofibrillary pathologies, synaptic dysfunction and neurodegeneration, and ultimately cognitive impairment
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig1: Multifactorial nature of AD and involvement of several different etiopathogenic mechanisms. Early-onset familial AD caused by mutations in APP, PS1, or PS2 constitutes < 1 % of AD cases. The exact causes of late-onset sporadic AD which accounts for the remaining > 99 % of AD cases are as yet largely unknown. However, aging alongside gene-environment interaction is speculated to contribute to this form of AD. Both forms of AD lead to amyloid plaque and neurofibrillary pathologies, synaptic dysfunction and neurodegeneration, and ultimately cognitive impairment
Mentions: AD, first described by German psychiatrist Alois Alzheimer in 1907 [37], is a multifactorial and heterogeneous disease, and apparently involves several different etiopathogenic mechanisms (Fig. 1) [6, 38]. The early-onset familial form of AD which is caused by mutations in amyloid β precursor protein (APP), presenilin 1 (PS1), or presenilin 2 (PS2), accounts for <1 % of all cases (Fig. 1) (for review, [39, 40]). The exact causes of the late-onset sporadic form of AD, which accounts for over 99 % of the cases, are not yet understood. The sporadic form of AD probably involves several different etiopathogenic mechanisms in concert with aging such as metabolic derangements, head trauma, metal ion toxicity, hypertension, vascular injury, smoking, psychological stress, and vitamin deficiencies (Fig. 1) [38]. No known mutations are involved in sporadic form of AD, however, the presence of one or two apolipoprotein E epsilon 4 (APOE ε4) alleles increases the disease risk ~3.5-fold or ~10-fold, respectively [39–41].Fig. 1

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