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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

Progression of neuropathology and cognitive impairment in AD. The earliest AD neuropathology develops in medial temporal lobe and gives rise to episodic memory deficit followed by impairment in semantic memory (preclinical AD). As the patient progresses to MCI stage, higher cognitive domains such as attention, executive function, visuospatial memory, and verbal recall become impaired. Also, general cognition starts to decline. As the patient progresses to mild to moderate AD stages, the neuropathology spreads to frontal and parietal lobes, and all cognitive domains become affected. In severe stage of AD, the neuropathology spreads to involve all brain lobes, and a profound deficit in all cognitive domains is noted
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Fig3: Progression of neuropathology and cognitive impairment in AD. The earliest AD neuropathology develops in medial temporal lobe and gives rise to episodic memory deficit followed by impairment in semantic memory (preclinical AD). As the patient progresses to MCI stage, higher cognitive domains such as attention, executive function, visuospatial memory, and verbal recall become impaired. Also, general cognition starts to decline. As the patient progresses to mild to moderate AD stages, the neuropathology spreads to frontal and parietal lobes, and all cognitive domains become affected. In severe stage of AD, the neuropathology spreads to involve all brain lobes, and a profound deficit in all cognitive domains is noted

Mentions: AD is a progressive neurodegenerative disorder (Fig. 3). As mentioned before, the earliest neuropathological changes in AD are in the hippocampus and entorhinal cortex, followed by changes in the medial temporal lobe [64–68]. Correspondingly, the earliest detectable cognitive deficit is in the medial temporal lobe dependent episodic memory [62, 69, 70]. Episodic memory deficits are followed by impairment in semantic memory; both memory domains depend on the neural circuitry of medial and lateral temporal lobes and occur prior to deficit in higher cognitive functions such as attention, and executive and visuospatial capabilities [71]. Mild deficits in executive functioning are first detectable near the end of the preclinical phase of AD [72, 73]. As the patient progresses from preclinical stage of AD into MCI, more cognitive functions begin to be impaired including verbal recall and deterioration of general memory domain [71, 74]. As the patient progresses from MCI into mild, moderate, and subsequently the severe stages of AD, general cognition continues to decline with impairment manifesting in all cognitive domains [75].Fig. 3


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

Kazim SF, Iqbal K - Mol Neurodegener (2016)

Progression of neuropathology and cognitive impairment in AD. The earliest AD neuropathology develops in medial temporal lobe and gives rise to episodic memory deficit followed by impairment in semantic memory (preclinical AD). As the patient progresses to MCI stage, higher cognitive domains such as attention, executive function, visuospatial memory, and verbal recall become impaired. Also, general cognition starts to decline. As the patient progresses to mild to moderate AD stages, the neuropathology spreads to frontal and parietal lobes, and all cognitive domains become affected. In severe stage of AD, the neuropathology spreads to involve all brain lobes, and a profound deficit in all cognitive domains is noted
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: Progression of neuropathology and cognitive impairment in AD. The earliest AD neuropathology develops in medial temporal lobe and gives rise to episodic memory deficit followed by impairment in semantic memory (preclinical AD). As the patient progresses to MCI stage, higher cognitive domains such as attention, executive function, visuospatial memory, and verbal recall become impaired. Also, general cognition starts to decline. As the patient progresses to mild to moderate AD stages, the neuropathology spreads to frontal and parietal lobes, and all cognitive domains become affected. In severe stage of AD, the neuropathology spreads to involve all brain lobes, and a profound deficit in all cognitive domains is noted
Mentions: AD is a progressive neurodegenerative disorder (Fig. 3). As mentioned before, the earliest neuropathological changes in AD are in the hippocampus and entorhinal cortex, followed by changes in the medial temporal lobe [64–68]. Correspondingly, the earliest detectable cognitive deficit is in the medial temporal lobe dependent episodic memory [62, 69, 70]. Episodic memory deficits are followed by impairment in semantic memory; both memory domains depend on the neural circuitry of medial and lateral temporal lobes and occur prior to deficit in higher cognitive functions such as attention, and executive and visuospatial capabilities [71]. Mild deficits in executive functioning are first detectable near the end of the preclinical phase of AD [72, 73]. As the patient progresses from preclinical stage of AD into MCI, more cognitive functions begin to be impaired including verbal recall and deterioration of general memory domain [71, 74]. As the patient progresses from MCI into mild, moderate, and subsequently the severe stages of AD, general cognition continues to decline with impairment manifesting in all cognitive domains [75].Fig. 3

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