PMID- 27400746
OWN - NLM
STAT- MEDLINE
DCOM- 20171109
LR  - 20240325
IS  - 1750-1326 (Electronic)
IS  - 1750-1326 (Linking)
VI  - 11
IP  - 1
DP  - 2016 Jul 11
TI  - Neurotrophic factor small-molecule mimetics mediated neuroregeneration and 
      synaptic repair: emerging therapeutic modality for Alzheimer's disease.
PG  - 50
LID - 10.1186/s13024-016-0119-y [doi]
LID - 50
AB  - 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 beta (Abeta) plaques and neurofibrillary tangles composed of 
      Abeta 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 Abeta 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-3beta (GSK-3beta, 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.
FAU - Kazim, Syed Faraz
AU  - Kazim SF
AD  - 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.
AD  - Graduate Program in Neural and Behavioral Science, and Department of Physiology 
      and Pharmacology, State University of New York (SUNY) Downstate Medical Center, 
      450 Clarkson Avenue, Brooklyn, NY, 11203, USA.
FAU - Iqbal, Khalid
AU  - Iqbal K
AD  - 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. khalid.iqbal.ibr@gmail.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20160711
PL  - England
TA  - Mol Neurodegener
JT  - Molecular neurodegeneration
JID - 101266600
RN  - 0 (Amyloid beta-Peptides)
SB  - IM
MH  - Alzheimer Disease/*metabolism
MH  - Amyloid beta-Peptides/*metabolism
MH  - Animals
MH  - Brain/*metabolism
MH  - Humans
MH  - Neurofibrillary Tangles/*metabolism
MH  - Neurogenesis/*physiology
MH  - Neurons/*metabolism
PMC - PMC4940708
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - Amyloid beta
OT  - Brain-derived neurotrophic factor (BDNF)
OT  - Ciliary neurotrophic factor (CNTF)
OT  - Cognition
OT  - Neurodegeneration
OT  - Neurogenesis
OT  - Neurotrophic factor small-molecule mimetics
OT  - Synaptic loss
OT  - Tau
EDAT- 2016/07/13 06:00
MHDA- 2017/11/10 06:00
PMCR- 2016/07/11
CRDT- 2016/07/13 06:00
PHST- 2016/04/24 00:00 [received]
PHST- 2016/07/02 00:00 [accepted]
PHST- 2016/07/13 06:00 [entrez]
PHST- 2016/07/13 06:00 [pubmed]
PHST- 2017/11/10 06:00 [medline]
PHST- 2016/07/11 00:00 [pmc-release]
AID - 10.1186/s13024-016-0119-y [pii]
AID - 119 [pii]
AID - 10.1186/s13024-016-0119-y [doi]
PST - epublish
SO  - Mol Neurodegener. 2016 Jul 11;11(1):50. doi: 10.1186/s13024-016-0119-y.